TW202231659A - Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers - Google Patents
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Abstract
Description
本發明涉及用於免疫治療方法的肽、蛋白質、核酸和細胞。特別是,本發明涉及癌症的免疫療法。本發明還涉及單獨使用或與其他腫瘤相關肽(刺激抗腫瘤免疫反應或體外刺激 T 細胞和轉入患者的疫苗複合物的活性藥物成分)聯合使用的腫瘤相關 T 細胞 (CTL) 肽表位。與主要組織相容性複合體 (MHC) 分子結合的肽或與此同類的肽也可能是抗體、可溶性 T 細胞受體和其他結合分子的靶標。The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapy methods. In particular, the present invention relates to immunotherapy of cancer. The present invention also relates to tumor associated T cell (CTL) peptide epitopes used alone or in combination with other tumor associated peptides (active pharmaceutical ingredients that stimulate antitumor immune responses or stimulate T cells in vitro and vaccine complexes that are transferred into patients). Peptides that bind major histocompatibility complex (MHC) molecules or similar peptides may also be targets of antibodies, soluble T-cell receptors, and other binding molecules.
本發明涉及數種新型肽序列及其變體,它們源自人腫瘤細胞的 HLA-I 類分子,可用于引發抗腫瘤免疫反應的疫苗組合物中或作為開發藥物/免疫活性化合物和細胞的目標。The present invention relates to several novel peptide sequences and variants thereof, derived from HLA class I molecules of human tumor cells, which can be used in vaccine compositions to elicit anti-tumor immune responses or as targets for the development of pharmaceutical/immunologically active compounds and cells .
胰腺癌是世界上侵襲性和致死性最高的癌症之一。2012 年,它是男性中第 12 大常見癌症,全世界有 178,000 名病例,女性中第 11 大常見癌症,全世界有 160,000 名病例。同年,報告了 330,000 萬例死亡病例,使胰腺癌成為第七大最常見癌症死因 (World Cancer Report, 2014)。Pancreatic cancer is one of the most aggressive and lethal cancers in the world. In 2012, it was the 12th most common cancer in men with 178,000 cases worldwide and the 11th most common cancer in women with 160,000 cases worldwide. In the same year, 330,000 deaths were reported, making pancreatic cancer the seventh most common cause of cancer death (World Cancer Report, 2014).
胰腺癌並非單一癌症實體,而是若干不同亞型必須加以區別。外分泌腫瘤占所有胰腺癌的 95% 左右,包括導管癌和腺泡狀腺癌、導管內乳頭狀黏液性腫瘤 (IPMN)、假乳頭狀實體瘤、囊性黏液腺瘤和漿液性囊腺瘤。其餘 5% 的胰腺癌屬於胰腺神經內分泌腫瘤的亞組 (World Cancer Report, 2014)。Pancreatic cancer is not a single cancer entity, but several distinct subtypes must be distinguished. Exocrine tumors account for approximately 95% of all pancreatic cancers and include ductal and acinar adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), pseudopapillary solid tumors, cystic mucinous adenomas, and serous cystadenomas. The remaining 5% of pancreatic cancers belong to the subgroup of pancreatic neuroendocrine tumors (World Cancer Report, 2014).
浸潤性導管腺癌代表最侵襲形式的胰腺癌,由於其高發頻率(90% 的胰腺癌),流行病學資料主要反映這一特定亞型 (World Cancer Report, 2014)。Invasive ductal adenocarcinoma represents the most aggressive form of pancreatic cancer, and due to its high frequency (90% of pancreatic cancers), epidemiological data mainly reflect this specific subtype (World Cancer Report, 2014).
2012 年,68% 的所有新病例發生在發達國家,以歐洲中部和東部、北美、阿根廷、烏拉圭和澳大利亞發病率最高。相反,非洲和東亞大多數國家顯示發病率較低。在全球範圍內,隨著時間變化兩性中的發病率似乎相當穩定 (World Cancer Report, 2014)。In 2012, 68% of all new cases occurred in developed countries, with the highest rates in central and eastern Europe, North America, Argentina, Uruguay and Australia. In contrast, most countries in Africa and East Asia show lower incidence. Globally, the incidence in both sexes appears to be fairly stable over time (World Cancer Report, 2014).
由於缺乏特異性症狀,胰腺癌通常在確診時已是晚期,往往已經處於轉移期。一經診斷,預後很差,5 年生存率為 5%,死亡率與發病率比例為 0.98 (World Cancer Report, 2014)。Due to the lack of specific symptoms, pancreatic cancer is usually diagnosed at an advanced stage and is often already in the metastatic stage. Once diagnosed, the prognosis is poor, with a 5-year survival rate of 5% and a mortality-to-morbidity ratio of 0.98 (World Cancer Report, 2014).
據報告,幾個因素可增加發生胰腺癌的風險,包括較大年齡(因為大多數患者在診斷時均為 65 歲以上)和種族(如,在美國,黑種人口與白種人口相比風險增加 1.5 倍)。進一步的風險因素為吸煙、身體肥胖、糖尿病、非 O 型 ABO 血型、胰腺炎和胰腺癌家族史 (World Cancer Report, 2014)。Several factors have been reported to increase the risk of developing pancreatic cancer, including older age (since most patients are over 65 years of age at diagnosis) and ethnicity (eg, in the United States, the black population has an increased risk compared with the white population) 1.5 times). Further risk factors are smoking, physical obesity, diabetes, non-O ABO blood group, pancreatitis and family history of pancreatic cancer (World Cancer Report, 2014).
高達 10% 的所有胰腺癌病例被認為有家族基礎。下列基因胚系突變與發生胰腺癌的風險增加有關:P16/CDKN2A、BRCA2、PALB2、PRSS1、STK11、ATM 和 DNA 錯配修復基因。此外,胰腺癌散發病例的特徵還在於不同原癌基因和腫瘤抑制基因的突變。導管腺癌最常見的基因突變發生于癌基因 KRAS (95% ) 和 AIB1(高達 60%)和腫瘤抑制基因TP53 (75%)、p16/CDKN2A (95%) 和 SMAD4 (55%) 內 (World Cancer Report, 2014)。Up to 10% of all pancreatic cancer cases are considered to have a familial basis. Germline mutations in the following genes are associated with an increased risk of developing pancreatic cancer: P16/CDKN2A, BRCA2, PALB2, PRSS1, STK11, ATM, and DNA mismatch repair genes. In addition, sporadic cases of pancreatic cancer are also characterized by mutations in different proto-oncogenes and tumor suppressor genes. The most common genetic mutations in ductal adenocarcinoma occur in the oncogenes KRAS (95%) and AIB1 (up to 60%) and the tumor suppressor genes TP53 (75%), p16/CDKN2A (95%) and SMAD4 (55%) (World Cancer Report, 2014).
胰腺癌患者的治療選擇非常有限。有效治療的一個主要問題是在確診時通常處於腫瘤晚期。此外,胰腺癌對化療藥物相當耐藥,這可能是由緻密和少血管結締組織增生腫瘤間質引起的。Treatment options for pancreatic cancer patients are very limited. A major problem with effective treatment is that the tumor is often at an advanced stage at the time of diagnosis. In addition, pancreatic cancer is quite resistant to chemotherapeutic drugs, which may be caused by a dense and hypovascular desmoplastic stroma.
根據德國抗癌協會、德國癌症援助組織和德國科學醫學協會發佈的指導方針,切除腫瘤是唯一可用的有效治療選擇。如果腫瘤局限於胰腺或如果只轉移到鄰近器官,則建議切除。如果腫瘤已經擴散到遠處部位,則不建議手術切除。切除後,用吉西他濱或 5-氟尿嘧啶+/-亞葉酸進行六個月的輔助化療 (S3-Leitlinie Exokrines Pankreaskarzinom, 2013)。According to guidelines issued by the German Association for Cancer Fighting, the German Cancer Aid and the German Scientific and Medical Association, tumor resection is the only effective treatment option available. Resection is recommended if the tumor is confined to the pancreas or if it has metastasized only to adjacent organs. Surgical removal is not recommended if the tumor has spread to distant sites. Following resection, adjuvant chemotherapy with gemcitabine or 5-fluorouracil +/- folinic acid was administered for six months (S3-Leitlinie Exokrines Pankreaskarzinom, 2013).
晚期不能手術的腫瘤患者可以透過化療與放化療聯合治療 (S3-Leitlinie Exokrines Pankreaskarzinom, 2013)。Patients with advanced inoperable tumors can be treated with a combination of chemotherapy and chemoradiotherapy (S3-Leitlinie Exokrines Pankreaskarzinom, 2013).
姑息化療標準方案為吉西他濱單藥療法或與表皮生長因數受體酪氨酸激酶抑制劑厄洛替尼聯合治療。替代方案是 5-氟尿嘧啶、甲醯四氫葉酸、依立替康和奧沙利鉑聯合(也稱為 FOLFIRINOX 方案),或吉西他濱與白蛋白結合型紫杉醇聯合(在 MPACT 研究中與吉西他濱單一療法相比顯示具有較優的療效 (Von Hoff et al., 2013; S3-Leitlinie Exokrines Pankreaskarzinom, 2013)。The standard regimen of palliative chemotherapy is gemcitabine monotherapy or in combination with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. Alternatives are the combination of 5-fluorouracil, tetrahydrofolate, irinotecan, and oxaliplatin (also known as the FOLFIRINOX regimen), or gemcitabine in combination with nab-paclitaxel (compared to gemcitabine monotherapy in the MPACT study) Shows superior efficacy (Von Hoff et al., 2013; S3-Leitlinie Exokrines Pankreaskarzinom, 2013).
死亡率與發病率高比例反映了實施更有效胰腺癌治療策略的迫切需要。The high mortality to morbidity ratio reflects the urgent need to implement more effective pancreatic cancer treatment strategies.
靶向治療已經在其他幾種癌症中顯示出效果,代表著一個令人關注的選項。因此,已經完成了一些研究來評估靶向治療對晚期胰腺癌的利益,遺憾的是,成果非常有限 (Walker and Ko, 2014)。儘管如此,胰腺癌的遺傳多樣性可能帶來個性化療法的可能性,因為 BRCA2 或 PALB2 等位基因失活的浸潤性導管腺癌被證明對聚(ADP-核糖)聚合酶抑制劑和絲裂黴素 C 治療更為敏感 (World Cancer Report, 2014)。Targeted therapy has already shown efficacy in several other cancers and represents an interesting option. Therefore, several studies have been completed to evaluate the benefit of targeted therapy in advanced pancreatic cancer, with unfortunately very limited results (Walker and Ko, 2014). Nonetheless, the genetic diversity of pancreatic cancer may present the possibility of personalized therapy, as invasive ductal adenocarcinomas with inactive BRCA2 or PALB2 alleles have been shown to be resistant to poly(ADP-ribose) polymerase inhibitors and mitogens. Mycin C treatment is more sensitive (World Cancer Report, 2014).
靶向作用於腫瘤間質構成了開發胰腺癌新療法的替代方法。典型的緻密和少血管間質可能充當化療劑的屏障,並且顯示可傳送促進腫瘤細胞增殖、侵襲和癌症幹細胞維持的信號。因此,不同的臨床前和臨床研究旨在分析基質消耗和失活的影響 (Rucki and Zheng, 2014)。Targeting the tumor stroma constitutes an alternative approach to developing new therapies for pancreatic cancer. The typically dense and hypovascular stroma may act as a barrier to chemotherapeutic agents and has been shown to transmit signals that promote tumor cell proliferation, invasion, and cancer stem cell maintenance. Therefore, different preclinical and clinical studies aimed to analyze the effects of matrix depletion and inactivation (Rucki and Zheng, 2014).
疫苗接種策略進行了研究,其作為胰腺癌治療的進一步創新和有前途的替代方法。基於肽的疫苗靶向作用於 KRAS 突變、活性端粒酶、胃泌素、存活蛋白、CEA 和 MUC1 已經在臨床試驗中進行評估,部分顯示有希望的結果。此外,針對胰腺癌患者的基於樹突狀細胞的疫苗、異基因 GM-CSF 分泌疫苗和 algenpantucel-L 臨床試驗還顯示了免疫療法的有益效果。進一步研究不同疫苗接種方案效率的臨床試驗目前正在進行中 (Salman et al., 2013)。Vaccination strategies were investigated as a further innovative and promising alternative for pancreatic cancer treatment. Peptide-based vaccines targeting KRAS mutations, active telomerase, gastrin, survivin, CEA, and MUC1 have been evaluated in clinical trials, with some showing promising results. In addition, clinical trials of dendritic cell-based vaccines, allogeneic GM-CSF secreted vaccines, and algenpantucel-L in pancreatic cancer patients have also shown beneficial effects of immunotherapy. Clinical trials to further investigate the efficacy of different vaccination regimens are currently underway (Salman et al., 2013).
考慮到治療癌症相關的嚴重副作用和費用,通常有必要確定可用於治療癌症的因數,尤其是胰腺癌。通常也有必要確定代表癌症生物標誌物的因數,尤其是胰腺癌,從而更好地診斷癌症、評估預後和預測治療成功性。Considering the serious side effects and costs associated with treating cancer, it is often necessary to identify factors that can be used to treat cancer, especially pancreatic cancer. It is also often necessary to identify factors that represent biomarkers of cancer, especially pancreatic cancer, to better diagnose cancer, assess prognosis, and predict treatment success.
癌症免疫治療代表了癌症細胞特異性靶向作用的一個選項,同時最大限度地減少副作用。癌症免疫療法利用存在的腫瘤相關抗原。Cancer immunotherapy represents an option for specific targeting of cancer cells while minimizing side effects. Cancer immunotherapy utilizes the presence of tumor-associated antigens.
腫瘤相關抗原 (TAA) 的目前分類主要包括以下幾組: a) 癌-睾丸抗原:T 細胞能夠識別的最先確認的 TAA 屬於這一類抗原,由於其成員表達于組織學相異的人腫瘤中、正常組織中、僅在睾丸的精母細胞/精原細胞中、偶爾在胎盤中,因此,它最初被稱為癌-睾丸 (CT) 抗原。由於睾丸細胞不表達 HLA I 類和 II 類分子,所以,在正常組織中,這些抗原不能被 T 細胞識別,因此在免疫學上可考慮為具有腫瘤特異性。CT 抗原大家熟知的例子是 MAGE 家族成員和 NY-ESO-1。 b) 分化抗原:腫瘤和正常組織(腫瘤源自該組織)都含有 TAA。大多數已知的分化抗原發現於黑色素瘤和正常黑色素細胞中。許多此類黑色素細胞譜系相關蛋白參與黑色素的生物合成,因此這些蛋白不具有腫瘤特異性,但是仍然被廣泛用於癌症的免疫治療。例子包括,但不僅限於,黑色素瘤的酪氨酸酶和 Melan-A/MART-1 或攝護腺癌的 PSA。 c) 過量表達的 TAA:在組織學相異的腫瘤中以及許多正常組織中都檢測到了基因編碼被廣泛表達的 TAA,一般表達水準較低。有可能許多由正常組織加工和潛在表現的表位低於 T 細胞識別的閾值水準,而它們在腫瘤細胞中的過量表達能夠通過打破先前確立的耐受性而引發抗癌反應。這類 TAA 的典型例子為 Her-2/neu、生存素、端粒酶或 WT1。 d) 腫瘤特異性抗原:這些獨特的 TAA 產生于正常基因(如 β-catenin、CDK4 等)的突變。這些分子變化中有一些與致瘤性轉化和/或進展相關。腫瘤特異性抗原一般可在不對正常組織帶來自體免疫反應風險的情況下誘導很強的免疫反應。另一方面,這些 TAA 在多數情況下只與其上確認了有 TAA 的確切腫瘤相關,並且通常在許多個體腫瘤之間並不都共用 TAA。在含有腫瘤特定(相關)同種型蛋白的情況下,如果肽源自腫瘤(相關)外顯子也可能出現肽腫瘤特異性(或相關性)。 e) 由異常翻譯後修飾產生的 TAA:此類 TAA 可能由腫瘤中既不具有特異性也不過量表達的蛋白產生,但其仍然具有腫瘤相關性(該相關性由主要對腫瘤具有活性的翻譯後加工所致)。此類 TAA 產生於變糖基化模式的改變,導致腫瘤產生針對 MUC1 的新型表位或在降解過程中導致諸如蛋白拼接的事件,這可能具有也可能不具有腫瘤特異性。 f) 腫瘤病毒蛋白:這些 TTA 是病毒蛋白,可在致癌過程中發揮關鍵作用,並且由於它們是外源蛋白(非人源蛋白),所以能夠激發 T 細胞反應。這類蛋白的例子有人乳頭狀瘤 16 型病毒蛋白、E6 和 E7,它們在宮頸癌中表達。 The current classification of tumor-associated antigens (TAAs) mainly includes the following groups: a) Cancer-testis antigens: The first identified TAAs recognized by T cells belong to this class of antigens, as their members are expressed in histologically distinct human tumors, in normal tissues, only in spermatocytes/spermatogenous cells of the testis cells and occasionally the placenta, so it was originally called the cancer-testis (CT) antigen. Since testicular cells do not express HLA class I and II molecules, these antigens cannot be recognized by T cells in normal tissues and are therefore immunologically considered tumor-specific. Well-known examples of CT antigens are MAGE family members and NY-ESO-1. b) Differentiation antigens: Both tumor and normal tissue from which the tumor originated contain TAA. Most of the known differentiation antigens are found in melanoma and normal melanocytes. Many of these melanocyte lineage-associated proteins are involved in melanin biosynthesis, so these proteins are not tumor-specific, but are still widely used in cancer immunotherapy. Examples include, but are not limited to, tyrosinase for melanoma and Melan-A/MART-1 or PSA for prostate cancer. c) Overexpressed TAAs: Genetically encoded widely expressed TAAs have been detected in histologically distinct tumors as well as in many normal tissues, generally at low levels. It is possible that many epitopes processed and potentially expressed by normal tissues are below the threshold level for T cell recognition, and their overexpression in tumor cells can elicit anticancer responses by breaking previously established tolerance. Typical examples of such TAAs are Her-2/neu, survivin, telomerase or WT1. d) Tumor-specific antigens: These unique TAAs arise from mutations in normal genes such as β-catenin, CDK4, etc. Some of these molecular changes are associated with tumorigenic transformation and/or progression. Tumor-specific antigens generally induce strong immune responses without the risk of an autologous immune response to normal tissues. On the other hand, these TAAs are in most cases only associated with the exact tumors on which TAAs have been identified, and TAAs are often not shared among many individual tumors. In the case of proteins containing tumor-specific (associated) isoforms, peptide tumor-specificity (or association) may also occur if the peptide is derived from tumor (associated) exons. e) TAAs produced by aberrant post-translational modifications: Such TAAs may be produced by proteins that are neither specific nor overexpressed in the tumor, but still have tumor-associated post-processing). Such TAAs arise from alterations in variable glycosylation patterns, leading tumors to develop novel epitopes against MUC1 or leading to events such as protein splicing during degradation, which may or may not be tumor specific. f) Tumor viral proteins: These TTAs are viral proteins that play a key role in carcinogenesis, and since they are foreign (non-human) proteins, they are capable of eliciting T cell responses. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical cancer.
基於 T 細胞的免疫治療靶向作用于主要組織相容性複合體 (MHC) 分子表現的來源於腫瘤相關蛋白或腫瘤特異性蛋白的肽表位。腫瘤特異性 T 淋巴細胞所識別的抗原,即其表位,可以是源自所有蛋白類型的分子,如酶、受體、轉錄因子等,它們在相應腫瘤的細胞中被表達,並且與同源未變的細胞相比,其表達通常上調。T cell-based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins expressed by major histocompatibility complex (MHC) molecules. Antigens recognized by tumor-specific T lymphocytes, i.e. their epitopes, can be molecules derived from all protein types, such as enzymes, receptors, transcription factors, etc., which are expressed in the cells of the corresponding tumor and are homologous to Its expression is generally up-regulated compared to unaltered cells.
MHC 分子有兩類:MHC I 類和 MHC II 類。MHC I 類分子由一條 α 重鏈和 β-2-微球蛋白,MHC II 類分子由一條 α 和一條 β 鏈組成。其三位構造形成一個結合槽,用於與肽進行非共價相互作用。There are two classes of MHC molecules: MHC class I and MHC class II. MHC class I molecules consist of an alpha heavy chain and beta-2-microglobulin, and MHC class II molecules consist of an alpha and a beta chain. Its three-dimensional configuration forms a binding groove for non-covalent interactions with peptides.
大部分有核細胞上都可發現 MHC-I 類分子。他們表現主要為內源性的蛋白、缺陷核糖體產物 (DRIP) 和較大肽裂解生成的肽。然而,源自內體結構或外源性來源的肽也經常在 MHC-I 類分子上發現。這種 I-類分子非經典表現方式在文獻中被稱為交叉表現 (Brossart and Bevan, 1997; Rock et al., 1990)。MHC II 類分子主要發現于專業抗原表現細胞 (APC) 上,並且主要表現,例如,在內吞作用過程中由 APC 佔據並且隨後被加工的外源性或跨膜蛋白的肽。MHC class I molecules are found on most nucleated cells. They manifest primarily as endogenous proteins, defective ribosomal products (DRIPs), and peptides resulting from cleavage of larger peptides. However, peptides derived from endosomal structures or from exogenous sources are also frequently found on MHC class I molecules. This non-classical representation of class I-molecules is referred to in the literature as cross-representation (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules are primarily found on professional antigen-presenting cells (APCs) and mainly express, for example, peptides of exogenous or transmembrane proteins that are occupied by APCs during endocytosis and subsequently processed.
肽和 MHC I 類的複合體由負載相應 T 細胞受體 (TCR) 的 CD8 陽性 T 細胞進行識別,而肽和 MHC II 類分子的複合體由負載相應 TCR 的 CD4 陽性輔助 T 細胞進行識別。因此,TCR、肽和 MHC 按照 1:1:1 的化學計量呈現,這一點已是共識。The peptide and MHC class I complexes are recognized by CD8-positive T cells loaded with the corresponding T-cell receptor (TCR), while the peptide and MHC class II complexes are recognized by CD4-positive helper T cells loaded with the corresponding TCR. Therefore, there is a consensus that TCR, peptide and MHC are presented in a 1:1:1 stoichiometry.
CD4 陽性輔助 T 細胞在誘導和維持 CD8 陽性細胞毒性 T 細胞的有效反應中發揮重要作用。腫瘤相關抗原 (TAA) 衍生的 CD4 陽性 T 細胞表位的識別對開發能引發抗腫瘤免疫反應的藥物產品可能非常重要 (Gnjatic et al., 2003)。在腫瘤部位,T 輔助細胞維持著對細胞毒性 T 細胞 (CTL) 友好的細胞因數環境 (Mortara et al., 2006) 並吸引效應細胞,如 CTL、天然殺傷 (NK) 細胞、巨噬細胞和粒細胞 (Hwang et al., 2007)。CD4-positive helper T cells play an important role in the induction and maintenance of an efficient response by CD8-positive cytotoxic T cells. The identification of tumor-associated antigen (TAA)-derived CD4-positive T-cell epitopes may be important for the development of drug products that elicit anti-tumor immune responses (Gnjatic et al., 2003). At tumor sites, T helper cells maintain a cytotoxic T cell (CTL)-friendly cytokine environment (Mortara et al., 2006) and attract effector cells such as CTLs, natural killer (NK) cells, macrophages, and granulocytes. cells (Hwang et al., 2007).
在沒有炎症的情況下,MHC II 類分子的表達主要局限於免疫系統細胞,尤其是專業抗原表現細胞 (APC),例如,單核細胞、單核細胞源性細胞、巨噬細胞、樹突狀細胞。在癌症患者的腫瘤細胞中發現有 MHC II 類分子的表達 (Dengjel et al., 2006)。In the absence of inflammation, expression of MHC class II molecules is largely restricted to immune system cells, especially professional antigen-presenting cells (APCs), e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells cell. Expression of MHC class II molecules has been found in tumor cells of cancer patients (Dengjel et al., 2006).
本發明的拉長肽可作為 MHC-II 類活性表位。The elongated peptides of the present invention can act as MHC-class II active epitopes.
MHC-II 類表位活化的輔助 T 細胞在編排抗腫瘤免疫的 CTL 效應子功能中發揮著重要作用。觸發 T H1細胞反應的輔助 T 細胞表位支援 CD8 陽性殺傷 T 細胞的效應子功能,其中包括直接作用於腫瘤細胞的細胞毒性功能(該類腫瘤細胞表面顯示有腫瘤相關肽/MHC 複合體)。這樣,腫瘤相關 T 輔助細胞表位單獨使用或與其他腫瘤相關肽結合使用可作為刺激抗腫瘤免疫反應的疫苗化合物的活性藥物成分。 Helper T cells activated by MHC class II epitopes play an important role in orchestrating CTL effector functions for antitumor immunity. Helper T cell epitopes that trigger TH1 cell responses support the effector functions of CD8-positive killer T cells, including cytotoxicity directly on tumor cells that display tumor-associated peptide/MHC complexes on their surface. Thus, tumor-associated T helper cell epitopes, alone or in combination with other tumor-associated peptides, can be used as active pharmaceutical ingredients in vaccine compounds that stimulate anti-tumor immune responses.
哺乳動物(如小鼠) 模型顯示,即使沒有 CD8 陽性 T 淋巴細胞,CD4 陽性 T 細胞也能通過分泌干擾素-γ (IFNγ) 抑制血管生成而足以抑制腫瘤的表現 (Beatty and Paterson, 2001; Mumberg et al., 1999)。沒有 CD4 T細胞作為直接抗腫瘤效應因數的證據 (Braumuller et al., 2013; Tran et al., 2014)。Mammalian (eg, mouse) models have shown that even in the absence of CD8-positive T lymphocytes, CD4-positive T cells are sufficient to suppress tumor manifestations by suppressing angiogenesis by secreting interferon-γ (IFNγ) (Beatty and Paterson, 2001; Mumberg et al., 1999). There is no evidence for CD4 T cells as a direct antitumor effector (Braumuller et al., 2013; Tran et al., 2014).
由於 HLA II 類分子的組成性表達通常僅限於免疫細胞,因此,直接從原發腫瘤中分離 II 類肽之前被認為是不可能的事。然而,Dengjel 等人成功地在腫瘤中直接識別了多個 MHC II 類表位 (WO 2007/028574, EP 1 760 088 B1)。Since constitutive expression of HLA class II molecules is usually restricted to immune cells, the direct isolation of class II peptides from primary tumors was previously thought to be impossible. However, Dengjel et al. succeeded in directly recognizing multiple MHC class II epitopes in tumors (WO 2007/028574,
由於 CD8 依賴型和 CD4 依賴型這兩種反應共同並協同地促進抗腫瘤作用,因此,確定和表徵由 CD8+ T 細胞(配體:MHC I 類分子 + 肽表位)或 CD4 陽性 T 輔助細胞(配體:MHC II 類分子)識別的腫瘤相關抗原對開發腫瘤疫苗非常重要。Since the two responses, CD8-dependent and CD4-dependent, jointly and synergistically promote antitumor effects, the identification and characterization of the antitumor effect by CD8+ T cells (ligand: MHC class I molecules + peptide epitopes) or CD4-positive T helper cells ( The tumor-associated antigens recognized by ligands: MHC class II molecules) are important for the development of tumor vaccines.
對於MHC I 類肽觸發(引發)細胞免疫反應的肽,它也必須與 MHC 分子結合。這一過程依賴於 MHC 分子的等位基因以及肽氨基酸序列的特異性多態性。MHC-I 類-結合肽的長度通常為 8-12 個氨基酸殘基,並且在其與 MHC 分子相應結合溝槽相互作用的序列中通常包含兩個保守殘基(「錨」)。這樣,每個 MHC 的等位基因都有「結合基序」,從而確定哪些肽能與結合溝槽特異性結合 。For an MHC class I peptide to trigger (elicit) a cellular immune response, it must also bind to the MHC molecule. This process relies on alleles of the MHC molecule and specific polymorphisms in the amino acid sequence of the peptide. MHC-class I-binding peptides are typically 8-12 amino acid residues in length and typically contain two conserved residues ("anchors") in their sequence that interact with the corresponding binding groove of the MHC molecule. In this way, each MHC allele has a "binding motif" that determines which peptides bind specifically to the binding groove.
在 MHC-I 類依賴性免疫反應中,肽不僅能與腫瘤細胞表達的某些 MHC-I 類分子結合,而且它們之後還必須能被 T 細胞負載的特異性 T 細胞受體 (TCR) 識別。In an MHC-class I-dependent immune response, not only can peptides bind to certain MHC-class I molecules expressed by tumor cells, but they must then be recognized by specific T cell receptors (TCRs) loaded by T cells.
對於被 T 淋巴細胞識別為腫瘤特異性抗原或相關性抗原以及用於治療的蛋白質,必須具備特殊的條件。該抗原應主要由腫瘤細胞表達,而不由正常健康組織表達,或表達數量相對較少。在一個優選的實施方案中,與正常健康組織相比,所述肽應在腫瘤細胞中過度表現。更為適宜的情況是,該相應抗原不僅出現於一種腫瘤中,而且濃度(即每個細胞的相應肽拷貝數目)高。腫瘤特異性抗原和腫瘤相關抗原往往是源自直接參與因細胞週期控制或凋亡抑制中的其功能而發生的正常細胞向腫瘤細胞轉化的蛋白。另外,這些直接導致轉化事件的蛋白的下游靶標可能會被上調,因此可能與腫瘤間接相關。這些間接腫瘤相關抗原也可能是預防接種方法的靶標 (Singh-Jasuja et al., 2004)。至關重要的是,表位存在於抗原氨基酸序列中,以確保這種來自腫瘤相關抗原的肽(「免疫原性肽」)可導致體外或體內 T 細胞反應。Special conditions must be met for proteins to be recognized by T lymphocytes as tumor-specific or associated antigens and for use in therapy. The antigen should be expressed predominantly by tumor cells and not by normal healthy tissue, or in a relatively small amount. In a preferred embodiment, the peptide should be overexpressed in tumor cells compared to normal healthy tissue. More suitably, the corresponding antigen is not only present in one tumor but also in high concentration (ie, the number of copies of the corresponding peptide per cell). Tumor-specific and tumor-associated antigens are often derived from proteins that are directly involved in the transformation of normal cells into tumor cells that occur as a result of their functions in cell cycle control or apoptosis inhibition. In addition, downstream targets of these proteins that directly lead to transformation events may be up-regulated and thus may be indirectly associated with tumors. These indirect tumor-associated antigens may also be targets for vaccination approaches (Singh-Jasuja et al., 2004). Crucially, the epitope is present in the antigenic amino acid sequence to ensure that such peptides from tumor-associated antigens ("immunogenic peptides") can elicit T cell responses in vitro or in vivo.
基本上,任何能與 MHC 分子結合的肽都可能充當一個 T 細胞表位。誘導體外或體內 T 細胞反應的前提是存在具有相應 TCR 的 T 細胞並且不存在對該特定表位的免疫耐受性。Basically, any peptide that can bind to an MHC molecule can potentially act as a T-cell epitope. A prerequisite for inducing a T cell response in vitro or in vivo is the presence of T cells with the corresponding TCR and the absence of immune tolerance to that particular epitope.
因此,TAA 是基於 T 細胞療法(包括但不限於腫瘤疫苗)研發的起點。識別和表徵 TAA 的方法通常基於對患者或健康受試者 T 細胞的使用情況,或基於腫瘤與正常組織肽之間差別轉錄特性或差別表達模式的產生。然而,對腫瘤組織或人腫瘤細胞株中過量表達或選擇性表達的基因的識別並不提供在免疫療法中使用這些基因所轉錄抗原的準確資訊。這是因為,有著相應 TCR 的 T 細胞必須要存在而且對這個特定表位的免疫耐受性必須不存在或為最低水準,因此,這些抗原的表位只有一部分適合這種應用。因此,在本發明的一非常優選的實施例中,只選擇那些針對可發現功能性和/或增殖性 T 細胞情況的過量表現或選擇性表現肽,這一點非常重要。這種功能性 T 細胞被定義為在以特異性抗原刺激後能夠克隆地擴展並能夠執行效應子功能(「效應子 T 細胞」)的 T 細胞。Therefore, TAA is the starting point for the development of T-cell-based therapies, including but not limited to tumor vaccines. Methods to identify and characterize TAAs are often based on the use of T cells from patients or healthy subjects, or on the generation of differential transcriptional properties or differential expression patterns between tumor and normal tissue peptides. However, the identification of genes that are overexpressed or selectively expressed in tumor tissues or human tumor cell lines does not provide accurate information on the antigens transcribed by these genes for use in immunotherapy. This is because T cells with the corresponding TCR must be present and immune tolerance to this particular epitope must be absent or minimal, so only a subset of these antigenic epitopes are suitable for this application. Therefore, in a highly preferred embodiment of the present invention, it is important to select only those peptides that are overexpressed or selectively expressed for situations where functional and/or proliferating T cells can be found. Such functional T cells are defined as T cells capable of clonally expanding and capable of performing effector functions ("effector T cells") upon stimulation with a specific antigen.
在通過根據本發明的特定 TCR(例如可溶性 TCR)和抗體或其他結合分子(支架)靶向作用於肽-MHC 的情況下,潛在肽的免疫原性是次要的。在這些情況下,表現是決定因素。In the case of targeting of peptide-MHCs by specific TCRs according to the invention (eg soluble TCRs) and antibodies or other binding molecules (scaffolds), the immunogenicity of the underlying peptides is of secondary importance. In these cases, performance is the deciding factor.
在本發明的第一方面,本發明涉及一種肽,包含選自包括 SEQ ID NO:1 至 SEQ ID NO:161 的組的一個氨基酸序列、或該序列的與 SEQ ID NO:1 至 SEQ ID NO:161 具有至少 77%,優選至少 88% 同源(優選至少 77% 或至少 88% 相同)的一種變體序列(其中所述變體與 MHC 結合和/或誘導 T 細胞與所述肽發生交叉反應),或其藥用鹽(其中所述肽不是潛在全長多肽)。In a first aspect of the invention, the invention relates to a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 161, or a combination of this sequence with SEQ ID NO: 1 to SEQ ID NO : 161 has at least 77%, preferably at least 88% homology (preferably at least 77% or at least 88% identical) a variant sequence (wherein said variant binds to MHC and/or induces T cell crossover with said peptide) reaction), or a pharmaceutically acceptable salt thereof (wherein the peptide is not a potential full-length polypeptide).
本發明進一步涉及本發明的一種肽,包含選自包括 SEQ ID NO:1 至 SEQ ID NO:161 的組的一個序列、或與 SEQ ID NO:1 至 SEQ ID NO:161 具有至少 77%、優選至少 88% 同源性(優選為至少 77% 或至少 88% 相同)的一種變體,其中所述肽或其變體的總長度為 8 至 100 個、優選為 8 至 30 個、最優選為 8 至 14 個氨基酸。The present invention further relates to a peptide of the invention comprising a sequence selected from the group comprising SEQ ID NO: 1 to SEQ ID NO: 161, or having at least 77%, preferably at least 77% with SEQ ID NO: 1 to SEQ ID NO: 161 A variant of at least 88% homology (preferably at least 77% or at least 88% identical), wherein the peptide or variant thereof has a total length of 8 to 100, preferably 8 to 30, most preferably 8 to 14 amino acids.
下表顯示了根據本發明的肽、它們各自的 SEQ ID NO、以及這些肽的可能源(潛在)基因。表 1 和表 2 中的所有肽均與 HLA-A*02 結合。表 2 中的肽之前在大型列表中披露,作為高通量篩查結果,錯誤率高,或使用演算法計算出,但之前與癌症毫無關聯。表 3 中的肽是可與本發明其他肽組合使用的其他肽。表 4 中的肽還可用於診斷和/或治療各種其他惡性疾病,這些疾病涉及過量表達或過度表現各潛在多肽。
表 1 : 本發明中的肽
本發明還一般涉及本發明的肽用於治療增殖性疾病,例如,肺癌、腎癌、腦癌、胃癌、結腸或直腸癌、肝癌、攝護腺癌、白血病、乳腺癌、梅克爾細胞癌 (MCC)、黑色素瘤、卵巢癌、食管癌、膀胱癌、子宮內膜癌、膽囊癌和膽管癌。The present invention also generally relates to the use of the peptides of the present invention for the treatment of proliferative diseases, eg, lung, kidney, brain, gastric, colon or rectal, liver, prostate, leukemia, breast, Merkel cell carcinoma ( MCC), melanoma, ovarian, esophageal, bladder, endometrial, gallbladder, and bile duct cancers.
特別優選的是本發明的肽(單獨或組合),其選自包括 SEQ ID NO:1 至 SEQ ID NO:161 的組。更優選的是所述肽(單獨或組合)選自包括 SEQ ID NO:1 至 SEQ ID NO:79(見表 1)的組,並且其用於胰腺癌、肺癌、腎癌、腦癌、胃癌、結腸或直腸癌、肝癌、攝護腺癌、白血病、乳腺癌、梅克爾細胞癌 (MCC)、黑色素瘤、卵巢癌、食管癌、膀胱癌、子宮內膜癌、膽囊癌和膽管癌、優選為胰腺癌的免疫治療。Particularly preferred are peptides of the invention (alone or in combination) selected from the group comprising SEQ ID NO: 1 to SEQ ID NO: 161. More preferably the peptides (alone or in combination) are selected from the group comprising SEQ ID NO: 1 to SEQ ID NO: 79 (see Table 1), and are used in pancreatic cancer, lung cancer, kidney cancer, brain cancer, gastric cancer , colon or rectal cancer, liver cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma (MCC), melanoma, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, gallbladder cancer and bile duct cancer, preferably Immunotherapy for pancreatic cancer.
如示下面的表 4 所示,其中本發明的許多肽也發現於其他腫瘤中,因此也可用於其他適應症的免疫治療。另請參閱圖 1 和實例 1。
表 4A :本發明的 肽及其在其他增殖性疾病(特別是其他癌性疾病)中的特定用途。該表顯示,對於其他腫瘤類型的選定肽,發現他們過量表現(特定表現)於 5% 以上測定的腫瘤樣本,或表現於 5% 以上測定的腫瘤樣本且幾何學平均值腫瘤與正常組織的比值大於 3。過度表現定義為與最高表現的正常樣本相比,腫瘤樣本中的表現更高。
因此,本發明的另一個方面涉及根據 SEQ 序列號 4、5、8、14、19、22、29、30、31、35、37、46、60、69、70、79、85、90、92、95、101、102、118、123、124、125、128、131、136、138、142、147、149、150、151、154、158、160、167、6、9、21、84、85、94、96、99、111、113、114、116、129、134、152、159 和 169 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療非小細胞肺癌 (NSCLC)。Therefore, another aspect of the present invention relates to SEQ ID NOS , 95, 101, 102, 118, 123, 124, 125, 128, 131, 136, 138, 142, 147, 149, 150, 151, 154, 158, 160, 167, 6, 9, 21, 84, 85 At least one peptide of the invention according to any one of cell lung cancer (NSCLC).
因此,本發明的另一個方面涉及根據 SEQ 序列號 14、19、35、46、52、59、60、62、64、75、79、80、81、90、95、102、110、114、124、125、128、129、131、136、138、143、144、145、147、148、149、150、158、160、162、163、165、167、169、4、6、23、37、94、104 和 155 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療非小細胞肺癌 (NSCLC)。Therefore, another aspect of the present invention relates to SEQ ID NOS , 125, 128, 129, 131, 136, 138, 143, 144, 145, 147, 148, 149, 150, 158, 160, 162, 163, 165, 167, 169, 4, 6, 23, 37, 94 At least one peptide of the invention according to any one of , 104 and 155 is used in combination with a peptide of a preferred embodiment for the treatment of non-small cell lung cancer (NSCLC).
因此,本發明的另一個方面涉及根據 SEQ 序列號 13、14、29、46、84、115、147、162、175、12、30、38、75、95、99、111、130 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療腎癌。Therefore, another aspect of the present invention relates to any of SEQ ID NOs: One of the described at least one peptide of the invention is used in combination with a peptide of a preferred embodiment for the treatment of renal cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 16、17、29、34、39、63、67、81、93、94、98、102、104、106、113、114、115、116、122、129、138、146、151、159、161、166、167、169、172、11、14、19、70、71、83、87、99、112、123、126、132、152 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療腦癌。Thus, another aspect of the present invention relates to SEQ ID NOS , 129, 138, 146, 151, 159, 161, 166, 167, 169, 172, 11, 14, 19, 70, 71, 83, 87, 99, 112, 123, 126, 132, 152 and 160 One of the described at least one peptide of the invention is used in combination with a peptide of a preferred embodiment for the treatment of brain cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 31、32、68、84、88、95、97、117、120、121、147、174、4、9、41、77、149 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療胃癌。Therefore, another aspect of the present invention relates to any of SEQ ID NOs: One of the described at least one peptide of the invention is used in combination with a peptide of a preferred embodiment for the treatment of gastric cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 5、28、29、30、31、37、40、41、60、85、90、92、93、94、99、114、115、120、124、125、128、131、137、142、145、148、151、152、154、157、158、159、165、4、34、84、111、146、149 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療結腸和直腸癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 125, 128, 131, 137, 142, 145, 148, 151, 152, 154, 157, 158, 159, 165, 4, 34, 84, 111, 146, 149, and 160. At least one peptide of the invention is used in combination with a peptide of a preferred embodiment for the treatment of colon and rectal cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 4、5、14、19、31、35、37、48、50、51、60、64、70、73、80、85、86、96、99、100、101、102、103、104、111、114、115、116、120、123、124、125、129、131、132、135、136、137、142、145、146、148、149、150、155、158、159、160、161、165、167、169、174 和 176 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療肝癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 100, 101, 102, 103, 104, 111, 114, 115, 116, 120, 123, 124, 125, 129, 131, 132, 135, 136, 137, 142, 145, 146, 148, 149, 150 , 155, 158, 159, 160, 161, 165, 167, 169, 174 and 176 of the present invention in combination with a peptide of a preferred embodiment for the treatment of liver cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 2、8、10、22、31、39、46、79、86、104、111、123、130、142、156 和 167 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療胰腺癌。Therefore, another aspect of the present invention relates to according to any one of SEQ ID NOs: At least one peptide of the present invention is used in combination with a peptide of a preferred embodiment for the treatment of pancreatic cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 98、102、109、111、115、142、148、151 和 167中任一項所述的本發明的至少一種肽與一種優選實施方案中的肽聯合用於治療攝護腺癌。Thus, another aspect of the present invention relates to at least one peptide of the present invention according to any one of SEQ ID NOs Peptide combination for the treatment of prostate cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 7、22、48、62、71、81、83、94、95、104、110、122、144、145、147、149、150、152、154、159、160、161、171 和 176 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療白血病。Therefore, another aspect of the present invention relates to SEQ ID NOS , 159, 160, 161, 171 and 176 for use in the treatment of leukemia in combination with at least one peptide of the invention according to any one of the peptides of a preferred embodiment.
因此,本發明的另一個方面涉及根據 SEQ 序列號 3、4、21、29、30、32、52、57、65、67、84、93、99、102、103、106、108、111、114、117、120、123、126、127、128、139、140、142、143、148、151 和 158 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療 AML。Therefore, another aspect of the present invention relates to SEQ ID NOs: , 117, 120, 123, 126, 127, 128, 139, 140, 142, 143, 148, 151 and 158 of the invention in combination with a peptide of a preferred embodiment for use in therapy AML.
因此,本發明的另一個方面涉及根據 SEQ 序列號 4、6、84、91、99、107、114、118、127、130、142、155 和 158中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療 CLL。Therefore, another aspect of the present invention relates to at least one of the present invention according to any one of SEQ ID NOs: 4, 6, 84, 91, 99, 107, 114, 118, 127, 130, 142, 155 and 158 The peptide is used in combination with a peptide of a preferred embodiment for the treatment of CLL.
因此,本發明的另一個方面涉及根據 SEQ 序列號 2、4、8、9、16、22、26、31、35、37、41、59、77、79、84、90、93、99、110、137、142、150、169、175、29、42、60、69、70、75、80、82、86、95、111、120、124、127、128、129、138、144、149、151、155、158 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療乳腺癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 137, 142, 150, 169, 175, 29, 42, 60, 69, 70, 75, 80, 82, 86, 95, 111, 120, 124, 127, 128, 129, 138, 144, 149, 151 At least one peptide of the invention according to any one of , 155, 158 and 160 is used in combination with a peptide of a preferred embodiment for the treatment of breast cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 149、81、101、116 和 124 中任一項所述的本發明的至少一種肽與一種優選實施方案中的肽聯合用於治療梅克爾細胞癌 (MCC)。Accordingly, another aspect of the present invention relates to the use of at least one peptide of the present invention according to any one of
因此,本發明的另一個方面涉及根據 SEQ 序列號 14、17、19、34、37、45、46、52、85、92、95、96、107、113、114、115、118、124、131、138、146、149、150、155、157、158、161、165、169、1、5、6、9、12、16、18、21、22、23、25、28、29、31、32、44、55、56、57、58、60、61、65、66、67、68、75、84、87、88、90、93、94、97、99、106、111、116、117、120、121、123、127、128、129、130、132、133、134、135、137、139、142、143、156、159 和160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療黑色素瘤。Therefore, another aspect of the present invention relates to SEQ ID NOS , 138, 146, 149, 150, 155, 157, 158, 161, 165, 169, 1, 5, 6, 9, 12, 16, 18, 21, 22, 23, 25, 28, 29, 31, 32 , 44, 55, 56, 57, 58, 60, 61, 65, 66, 67, 68, 75, 84, 87, 88, 90, 93, 94, 97, 99, 106, 111, 116, 117, 120 At least one peptide of the invention described in any one of The peptide combinations of the embodiments are used in the treatment of melanoma.
因此,本發明的另一個方面涉及根據 SEQ 序列號 4、14、35、37、46、52、60、70、81、85、92、94、95、101、120、124、125、129、131、132、134、136、142、146、147、149、150、154、157、158、160、162、165、167、3、47、57、84、89、99、111、138 和 148 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療卵巢癌。Therefore, another aspect of the present invention relates to SEQ ID NOs: , 132, 134, 136, 142, 146, 147, 149, 150, 154, 157, 158, 160, 162, 165, 167, 3, 47, 57, 84, 89, 99, 111, 138 and 148 One of the described at least one peptide of the invention is used in combination with a peptide of a preferred embodiment for the treatment of ovarian cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 1、2、4、5、8、9、11、12、14、19、29、35、37、40、46、50、51、52、57、58、62、63、67、70、75、77、79、85、91、92、94、95、106、114、118、120、124、129、131、132、135、136、137、142、147、148、149、154、158、165、169、1、2、4、5、8、9、11、12、14、19、29、35、37、40、46、50、51、52、57、58、62、63、67、70、75、77、79、85、91、92、94、95、106、114、118、120、124、129、131、132、135、136、137、142、147、148、149、154、158、165 和 169中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療食管癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 58, 62, 63, 67, 70, 75, 77, 79, 85, 91, 92, 94, 95, 106, 114, 118, 120, 124, 129, 131, 132, 135, 136, 137, 142 , 147, 148, 149, 154, 158, 165, 169, 1, 2, 4, 5, 8, 9, 11, 12, 14, 19, 29, 35, 37, 40, 46, 50, 51, 52 , 57, 58, 62, 63, 67, 70, 75, 77, 79, 85, 91, 92, 94, 95, 106, 114, 118, 120, 124, 129, 131, 132, 135, 136, 137 At least one peptide of the invention according to any one of , 142, 147, 148, 149, 154, 158, 165 and 169 is used in combination with a peptide of a preferred embodiment for the treatment of esophageal cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 3、4、20、29、37、41、42、59、60、64、82、88、91、93、95、97、99、101、104、106、114、115、120、122、131、135、137、142、150、151、152、154、156、157、160、166、169、170、171、175、1、5、6、12、14、15、19、30、31、38、46、52、57、65、67、70、71、74、84、86、89、92、94、100、103、107、109、111、113、118、123、126、127、128、129、130、138、148、149、158 和 159 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療膀胱癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 106, 114, 115, 120, 122, 131, 135, 137, 142, 150, 151, 152, 154, 156, 157, 160, 166, 169, 170, 171, 175, 1, 5, 6, 12 , 14, 15, 19, 30, 31, 38, 46, 52, 57, 65, 67, 70, 71, 74, 84, 86, 89, 92, 94, 100, 103, 107, 109, 111, 113 , 118, 123, 126, 127, 128, 129, 130, 138, 148, 149, 158 and 159 in combination with at least one peptide of the invention in combination with a peptide of a preferred embodiment for the treatment of bladder cancer .
因此,本發明的另一個方面涉及根據 SEQ 序列號 41、85、94、116、120、130、143、162、165 和 166 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療子宮內膜癌。Therefore, another aspect of the present invention relates to at least one peptide of the present invention according to any one of SEQ SEQ ID NOs: 41, 85, 94, 116, 120, 130, 143, 162, 165 and 166 and a preferred embodiment The peptide combination for the treatment of endometrial cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 8、10、19、31、73、75、94、102、115、116、122、125、131、149、4、21、22、30、46、50、69、70、80、90、95、96、103、111、120、129、142、144、145、147、152、154、156 和 160 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療膽囊癌和膽管癌。Therefore, another aspect of the present invention relates to SEQ ID NOS at least one of the present inventions described in any one of The peptides are used in combination with the peptides of a preferred embodiment for the treatment of gallbladder cancer and bile duct cancer.
因此,本發明的另一個方面涉及根據 SEQ 序列號 4、5、6、12、14、15、19、29、37、38、39、42、46、50、56、57、60、70、74、82、84、91、95、101、103、104、106、110、111、118、123、129、132、135、146、148、149、151、156、157、158、159、160 和 161 中任一項所述的本發明的至少一種肽與一種優選實施方案的肽聯合用於治療子宮癌。Therefore, another aspect of the present invention relates to SEQ ID NOS , 82, 84, 91, 95, 101, 103, 104, 106, 110, 111, 118, 123, 129, 132, 135, 146, 148, 149, 151, 156, 157, 158, 159, 160 and 161 At least one of the peptides of the invention described in any one is used in combination with a peptide of a preferred embodiment for the treatment of uterine cancer.
因此,本發明的另一個方面涉及本發明中肽的用途 - 優選聯合用於治療選自胰腺癌、肺癌、腎癌、腦癌、胃癌、結腸或直腸癌、肝癌、攝護腺癌、白血病、乳腺癌、梅克爾細胞癌 (MCC)、黑色素瘤、卵巢癌、食管癌、膀胱癌、子宮內膜癌、膽囊癌和膽管癌組中的增殖性疾病。Therefore, another aspect of the present invention relates to the use of the peptides of the present invention - preferably in combination for the treatment of cancers selected from the group consisting of pancreatic, lung, kidney, brain, gastric, colon or rectal cancer, liver cancer, prostate cancer, leukemia, Proliferative disorders in the breast, Merkel cell carcinoma (MCC), melanoma, ovarian, esophageal, bladder, endometrial, gallbladder, and cholangiocarcinoma groups.
本發明還涉及本發明的肽,其具有與主要組織相容性複合體 (MHC) I 或以拉長形式存在的例如長度變化的- MHC-II 類分子結合的能力。The present invention also relates to peptides of the present invention which have the ability to bind to major histocompatibility complex (MHC) I or to e.g. length-variable -MHC-class II molecules in elongated form.
本發明進一步涉及本發明中的肽,其中所述肽(每種肽)系由或基本系由根據 SEQ ID NO:1 至 SEQ ID NO:161 的一個氨基酸序列組成。The present invention further relates to the peptides of the present invention, wherein said peptide (each peptide) consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 161.
本發明進一步涉及本發明的肽,其中所述肽被修飾和/或包含非肽鍵。The present invention further relates to the peptides of the invention, wherein the peptides are modified and/or comprise non-peptide bonds.
本發明進一步涉及本發明的肽,其中所述肽為融合蛋白的一部分,特別是與 HLA-DR 抗原相關不變鏈 (Ii) 的 N-端氨基酸融合,或與抗體(例如,樹突狀細胞特定抗體)或抗體的序列融合。The present invention further relates to the peptides of the present invention, wherein the peptides are part of a fusion protein, in particular fused to the N-terminal amino acid of the HLA-DR antigen-associated invariant chain (Ii), or to antibodies (eg, dendritic cells) specific antibodies) or sequence fusions of antibodies.
本發明進一步涉及一種核酸,其編碼本發明的肽。本發明進一步涉及一種本發明的核酸,為 DNA、cDNA、PNA、RNA,也可能為其組合物。The present invention further relates to a nucleic acid encoding the peptide of the present invention. The present invention further relates to a nucleic acid of the present invention, which is DNA, cDNA, PNA, RNA, and possibly a combination thereof.
本發明進一步涉及一種能表達和/或表達本發明核酸的表達載體。The present invention further relates to an expression vector capable of expressing and/or expressing the nucleic acid of the present invention.
本發明進一步涉及本發明的一種肽、本發明的一種核酸或本發明的一種治療疾病的藥用表達載體,特別是用於治療癌症。The present invention further relates to a peptide of the present invention, a nucleic acid of the present invention or a pharmaceutical expression vector of the present invention for the treatment of diseases, especially for the treatment of cancer.
本發明進一步涉及本發明中肽或本發明中所述肽複合體(含有 MHC)的特定抗體以及製造這些抗體的方法。The present invention further relates to specific antibodies of the peptides of the present invention or of the peptide complexes of the present invention (containing MHC) and methods of making these antibodies.
本發明進一步涉及本發明的 T 細胞受體 (TCR),特別是可溶性TCR (sTCRs) 和加工為自體或異體 T 細胞的克隆 TCR,以及製造這些 TCR 的方法和載有所述 TCR 或所述 TCR 交叉反應的 NK 細胞的製造方法。The present invention further relates to the T cell receptors (TCRs) of the present invention, in particular soluble TCRs (sTCRs) and cloned TCRs processed into autologous or allogeneic T cells, as well as methods of making these TCRs and carrying said TCRs or said TCRs Methods of manufacturing TCR cross-reactive NK cells.
抗體和 TCR 是根據本發明的肽現有免疫治療用途的另外實施方案。Antibodies and TCRs are further embodiments of existing immunotherapeutic uses of the peptides according to the invention.
本發明進一步涉及含本發明核酸或前述表達載體的一種宿主細胞。本發明進一步涉及本發明的宿主細胞,其為抗原表現細胞,優選為樹突細胞。The present invention further relates to a host cell containing the nucleic acid of the present invention or the aforementioned expression vector. The present invention further relates to the host cell of the present invention, which is an antigen-expressing cell, preferably a dendritic cell.
本發明進一步涉及配製本發明一種肽的一種方法,所述方法包括培養本發明的宿主細胞和從所述宿主細胞或其培養基中分離肽。The present invention further relates to a method of formulating a peptide of the present invention, the method comprising culturing a host cell of the present invention and isolating the peptide from the host cell or the culture medium thereof.
本發明進一步涉及本發明中的所述方法,其中抗原通過與足夠量的含抗原提成細胞的抗原結合被載入表達於合適抗原表現細胞或人工抗原呈遞細胞表面的 I 或 II 類 MHC 分子。The present invention further relates to the method of the present invention, wherein the antigen is loaded into MHC class I or II molecules expressed on the surface of a suitable antigen-expressing cell or artificial antigen-presenting cell by binding to a sufficient amount of antigen containing antigen-presenting cells.
本發明進一步涉及本發明的方法,其中抗原表現細胞由能表達含 SEQ ID NO.1 至 SEQ ID NO.161、優選為含 SEQ ID No. 1 至 SEQ ID No. 79 所述肽的一個表達載體、或一個變體氨基酸序列組成。The present invention further relates to the method of the present invention, wherein the antigen-expressing cell is composed of an expression vector capable of expressing a peptide comprising the peptides described in SEQ ID NO. , or a variant amino acid sequence composition.
本發明進一步涉及以本發明方法製造的啟動 T 細胞,其中所述 T 細胞有選擇性地識別一種細胞,該細胞表達含一種本發明氨基酸序列的多肽。The present invention further relates to prime T cells produced by the method of the present invention, wherein said T cells selectively recognize a cell expressing a polypeptide comprising an amino acid sequence of the present invention.
本發明進一步涉及一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明任何氨基酸序列的多肽,該方法包括給予患者按本發明方法製造的有效量 T 細胞。The present invention further relates to a method of killing target cells of a patient, wherein the target cells of the patient abnormally express a polypeptide comprising any of the amino acid sequences of the present invention, the method comprising administering to the patient an effective amount of T cells produced by the method of the present invention.
本發明進一步涉及任何所述肽、本發明的核酸、本發明的表達載體、本發明的細胞、本發明的作為藥劑或製造藥劑的啟動 T 淋巴細胞、T 細胞受體或抗體或其他肽-和/或肽-MHC 結合分子的用途。所述藥劑優選為具有抗癌活性。The invention further relates to any of said peptides, nucleic acids of the invention, expression vectors of the invention, cells of the invention, primed T lymphocytes, T cell receptors or antibodies or other peptides of the invention as medicaments or for the manufacture of medicaments - and /or use of peptide-MHC binding molecules. The agent preferably has anticancer activity.
優選情況為,所述藥劑為基於可溶性 TCR 或抗體的細胞治療藥物、疫苗或蛋白質。Preferably, the agent is a soluble TCR or antibody-based cell therapy drug, vaccine or protein.
本發明還一般涉及本發明的用途,其中所述癌細胞為胰腺癌、肺癌、腎癌、腦癌、胃癌、結腸或直腸癌、肝癌、攝護腺癌、白血病、乳腺癌、梅克爾細胞癌 (MCC)、黑色素瘤、卵巢癌、食管癌、膀胱癌、子宮內膜癌、膽囊癌和膽管癌,優選為胰腺癌細胞。The invention also generally relates to the use of the invention wherein the cancer cells are pancreatic, lung, kidney, brain, stomach, colon or rectal, liver, prostate, leukemia, breast, Merkel cell carcinomas (MCC), melanoma, ovarian, esophageal, bladder, endometrial, gallbladder and bile duct cancers, preferably pancreatic cancer cells.
本發明進一步涉及一種基於本發明肽的生物標誌物,在此成為「靶標」,其可用於診斷癌症,優選為胰腺癌。所述標誌物可以肽本身過度表現或相應基因過度表達。標誌物也可以用於預測治療成功的可能性,優選為免疫療法,最優選為靶向作用於該生物標誌物識別的相同靶標的免疫療法。例如,抗體或可溶性 TCR 可用於染色腫瘤切片以檢測是否存在相關肽與 MHC 複合。The present invention further relates to a biomarker, herein referred to as a "target", based on the peptides of the present invention, which can be used to diagnose cancer, preferably pancreatic cancer. The marker can be overexpressed by the peptide itself or by the overexpression of the corresponding gene. A marker can also be used to predict the likelihood of treatment success, preferably immunotherapy, and most preferably immunotherapy targeting the same target identified by the biomarker. For example, antibodies or soluble TCRs can be used to stain tumor sections to detect the presence of relevant peptides complexed with MHC.
或者,抗體具有進一步的效應子功能,如免疫刺激域或毒素。Alternatively, the antibody has further effector functions, such as immunostimulatory domains or toxins.
本發明還涉及這些癌症治療中新靶點的用途。The present invention also relates to the use of these novel targets in the treatment of cancer.
AAGAB 編碼與一種參與網格蛋白包被的小泡運輸複合物 γ-銜接蛋白和 α-銜接蛋白亞基相互作用的蛋白質。這種基因的突變與 I 型點狀掌蹠角化病相關 (RefSeq, 2002)。AAGAB 是 miR-205 的一個靶基因,miR-205 在子宮頸癌中過度表達 (Xie et al., 2012)。AAGAB 敲除導致細胞分裂和增殖增加 (Pohler et al., 2012)。AAGAB encodes a protein that interacts with the γ-adaptin and α-adaptin subunits of the clathrin-coated vesicle trafficking complex. Mutations in this gene are associated with type I punctate palmoplantar keratoderma (RefSeq, 2002). AAGAB is a target gene of miR-205, which is overexpressed in cervical cancer (Xie et al., 2012). AAGAB knockout resulted in increased cell division and proliferation (Pohler et al., 2012).
ACTR2 編碼 ARP2 肌動蛋白相關蛋白 2 同源物,其是 ARP2/3 複合體的主要成分。這種複合體透過片狀偽足肌動蛋白的裝配和突出對細胞形狀和運動性具有必不可少的作用 (RefSeq, 2002)。ARP2/3 與其他蛋白質的複合顯示在腫瘤細胞侵襲和遷移中起著至關重要的作用 (Nurnberg et al., 2011; Feldner and Brandt, 2002; Frugtniet et al., 2015; Kurisu and Takenawa, 2010; Kirkbride et al., 2011)。ARP2/3 複合體與 WASP/WAVE 蛋白家族成員促使乳腺癌細胞侵襲和轉移 (Frugtniet et al., 2015)。當胰腺癌細胞的黏附和遷移被限制時,ARP2/3 複合體與 ArgBP2 被賦予抗腫瘤功能 (Roignot and Soubeyran, 2009)。ACTR2 encodes the ARP2 actin-related protein 2 homolog, which is a major component of the ARP2/3 complex. The assembly and protrusion of this complex through lamellipodia actin is essential for cell shape and motility (RefSeq, 2002). ARP2/3 complexed with other proteins has been shown to play a critical role in tumor cell invasion and migration (Nurnberg et al., 2011; Feldner and Brandt, 2002; Frugtniet et al., 2015; Kurisu and Takenawa, 2010; Kirkbride et al., 2011). The ARP2/3 complex and members of the WASP/WAVE protein family promote breast cancer cell invasion and metastasis (Frugtniet et al., 2015). When the adhesion and migration of pancreatic cancer cells are restricted, the ARP2/3 complex and ArgBP2 confer antitumor functions (Roignot and Soubeyran, 2009).
ADAM9 編碼 ADAM(解聯蛋白和金屬蛋白酶結構域) 家族的一員(第 9 成員)。該家族的成員參與細胞-細胞和細胞-基質的相互作用 (RefSeq, 2002)。ADAM9 基因沉寂降低食管鱗狀細胞癌 (ESCC) 的癌增殖 (Liu et al., 2015b)。ADAM9 在黑色素瘤增殖和侵襲中起著重要作用 (Ebrahimi et al., 2014)。ADAM9 被證明在骨肉瘤細胞、肌層浸潤性 (MI) 膀胱癌細胞、非小細胞肺癌、胰腺癌、結腸癌、口腔鱗狀細胞癌、宮頸癌、攝護腺癌、腎癌、胃癌、淋巴結癌和乳腺癌中上調 (Shaker et al., 2011; Vincent-Chong et al., 2013; Li et al., 2013; Ebrahimi et al., 2014; Zhang et al., 2014a; Jia et al., 2014; O'Shea et al., 2003; Jiang et al., 2014a; Zubel et al., 2009)。ADAM9 牽涉肺癌轉移到大腦 (Sher et al., 2014; Lin et al., 2014a; Shintani et al., 2004)。ADAM9 encodes a member (member 9) of the ADAM (disintegrin and metalloproteinase domain) family. Members of this family are involved in cell-cell and cell-matrix interactions (RefSeq, 2002). ADAM9 gene silencing reduces cancer proliferation in esophageal squamous cell carcinoma (ESCC) (Liu et al., 2015b). ADAM9 plays an important role in melanoma proliferation and invasion (Ebrahimi et al., 2014). ADAM9 has been shown in osteosarcoma cells, muscle-invasive (MI) bladder cancer cells, non-small cell lung cancer, pancreatic cancer, colon cancer, oral squamous cell carcinoma, cervical cancer, prostate cancer, kidney cancer, gastric cancer, lymph node Upregulated in cancer and breast cancer (Shaker et al., 2011; Vincent-Chong et al., 2013; Li et al., 2013; Ebrahimi et al., 2014; Zhang et al., 2014a; Jia et al., 2014 ; O'Shea et al., 2003; Jiang et al., 2014a; Zubel et al., 2009). ADAM9 has been implicated in lung cancer metastasis to the brain (Sher et al., 2014; Lin et al., 2014a; Shintani et al., 2004).
AGAP9 編碼具有 GTP 酶結構域,錨蛋白重複和 PH 結構域 9 的 ArfGAP,位於染色體10q11.22上 (RefSeq, 2002)。AGAP9 encodes ArfGAP with a GTPase domain, ankyrin repeats and PH domain 9 and is located on chromosome 10q11.22 (RefSeq, 2002).
AHCY 編碼腺苷高半胱氨酸酶。它調節細胞內S-腺苷高半胱氨酸 (SAH) 濃度,被認為對於轉甲基作用反應是重要的 (RefSeq, 2002)。AHCY 下調有助於腫瘤發生 (Leal et al., 2008)。AHCY 能促進細胞凋亡。它能抑制食管鱗狀細胞癌的黏附和遷移,提示具有食管致癌作用 (Li et al., 2014b)。AHCY 蛋白表達在結腸癌中上調 (Kim et al., 2009; Watanabe et al., 2008; Fan et al., 2011)。AHCY 可能是卵巢癌的潛在生物標誌物 (Peters et al., 2005)。AHCY encodes adenosylhomocysteinase. It regulates intracellular S-adenosylhomocysteine (SAH) concentration and is thought to be important for the transmethylation response (RefSeq, 2002). Downregulation of AHCY contributes to tumorigenesis (Leal et al., 2008). AHCY can promote apoptosis. It inhibits the adhesion and migration of esophageal squamous cell carcinoma, suggesting an esophageal carcinogenesis (Li et al., 2014b). AHCY protein expression is upregulated in colon cancer (Kim et al., 2009; Watanabe et al., 2008; Fan et al., 2011). AHCY may be a potential biomarker for ovarian cancer (Peters et al., 2005).
AK2 編碼腺苷酸激酶 2。AK2 位於線粒體膜間隙,可能在凋亡中發揮作用 (RefSeq, 2002)。AK2 介導可能參與腫瘤發生的新內在凋亡途徑 (Lee et al., 2007)。AK2 encodes adenylate kinase 2. AK2 is located in the mitochondrial intermembrane space and may play a role in apoptosis (RefSeq, 2002). AK2 mediates a new intrinsic apoptotic pathway that may be involved in tumorigenesis (Lee et al., 2007).
ANKLE2 編碼錨蛋白重複和含 LEM 域 蛋白 2。ANKLE2 是 LEM 內核膜蛋白 LEM 家族的一員。所編碼的蛋白透過核膜的有絲分裂後形成而充當有絲分裂調節蛋白 (RefSeq, 2002)。ANKLE2 encodes ankyrin repeats and LEM domain-containing protein 2. ANKLE2 is a member of the LEM family of LEM nuclear membrane proteins. The encoded protein is formed after mitosis through the nuclear envelope and acts as a mitotic regulator protein (RefSeq, 2002).
ANKRD1 編碼錨蛋白重複域 1。它位於內皮細胞的細胞核,由 IL-1 和 TNF-α 刺激誘導。該蛋白質與肌節蛋白肌鈀蛋白和肌聯蛋白之間的相互作用表明,它也可能參與肌原纖維拉伸感測器系統 (RefSeq, 2002)。ANKRD1 的異位表達導致集落形成減少,並增強肝癌細胞凋亡 (Park et al., 2005)。卵巢癌中 ANKRD1 的高表達與不良預後相關 (Lei et al., 2015)。ANKRD1 encodes
ANLN 編碼一種在細胞生長和遷移以及胞質分裂中發揮作用的肌動蛋白結合蛋白。ANLN 被認為可調節足細胞(腎小球的組成部分)的肌動蛋白骨架動力學。這種基因的突變與局灶節段性腎小球硬化 8 (RefSeq, 2002)。ANLN 被發現在乳腺癌組織以及頭頸部鱗狀細胞癌中高表達。ANLN 的敲除明顯抑制乳腺癌細胞的增殖率、集落形成能力和遷移 (Zhou et al., 2015b)。ANLN 在增殖性胃腫瘤、胰腺癌和激素難治性攝護腺癌中過度表達 (Pandi et al., 2014; Tamura et al., 2007; Shimizu et al., 2007; Olakowski et al., 2009)。ANLN 是肝細胞癌的一種生物標誌物 (Kim et al., 2013a)。ANLN 表達是腎細胞癌患者預後良好的標誌 (Ronkainen et al., 2011)。ANLN encodes an actin-binding protein that plays a role in cell growth and migration, as well as cytokinesis. ANLN is thought to regulate actin cytoskeleton dynamics in podocytes, a component of the glomerulus. Mutations in this gene are associated with focal segmental glomerulosclerosis 8 (RefSeq, 2002). ANLN was found to be highly expressed in breast cancer tissues as well as in head and neck squamous cell carcinomas. Knockdown of ANLN significantly inhibited the proliferation rate, colony-forming ability and migration of breast cancer cells (Zhou et al., 2015b). ANLN is overexpressed in proliferative gastric tumors, pancreatic cancer, and hormone-refractory prostate cancer (Pandi et al., 2014; Tamura et al., 2007; Shimizu et al., 2007; Olakowski et al., 2009). ANLN is a biomarker for hepatocellular carcinoma (Kim et al., 2013a). ANLN expression is a marker of good prognosis in renal cell carcinoma patients (Ronkainen et al., 2011).
APOL6 編碼載脂蛋白 L,6。APOL6 是載脂蛋白 L 基因家族的一員。所編碼的蛋白存在於細胞質中,在那裏它可能會影響脂質的運動或讓脂質結合至細胞器 (RefSeq, 2002)。 APOL6 在癌細胞中誘導線粒體介導的凋亡 (Liu et al., 2005)。APOL6 encodes apolipoprotein L,6. APOL6 is a member of the apolipoprotein L gene family. The encoded protein resides in the cytoplasm, where it may affect lipid movement or allow lipid binding to organelles (RefSeq, 2002). APOL6 induces mitochondria-mediated apoptosis in cancer cells (Liu et al., 2005).
ARMC9(也稱為 KU-MEL-1)編碼含犰狳重複基因蛋白,這是在黑色素細胞中優先表達的先前分離的黑色素瘤抗原。它與沃格特-小柳-原田(Vogt-Koyanagi-Harada)疾病相關 (Otani et al., 2006)。ARMC9 在黑色素瘤細胞系和組織樣本中強烈表達。抗ARMC9抗原在接受腦、結腸和食道癌治療的患者血清中檢測到 (Kiniwa et al., 2001)。ARMC9 (also known as KU-MEL-1) encodes the armadillo repeat-containing protein, a previously isolated melanoma antigen that is preferentially expressed in melanocytes. It is associated with Vogt-Koyanagi-Harada disease (Otani et al., 2006). ARMC9 is strongly expressed in melanoma cell lines and tissue samples. Anti-ARMC9 antigen was detected in the serum of patients treated for brain, colon and esophageal cancer (Kiniwa et al., 2001).
ASNS 編碼天冬醯胺合成酶。ASNS 基因補足溫度敏感型倉鼠突變 ts11 的突變,這在非容許溫度下阻斷其進展至細胞週期的 G1 期 (RefSeq, 2002)。ASNS 表達由葡萄糖剝奪誘導,保護胰腺癌細胞免於凋亡 (Cui et al., 2007)。ASNS 與白血病和子宮癌的耐藥性相關 (Lin et al., 2012; Zhang et al., 2013a)。A375 細胞中的 ASNS 敲除下調 CDK4、CDK6 和細胞週期蛋白 D1 的表達水準,上調 p21 的表達 (Li et al., 2015a)。ASNS 下調誘導細胞週期停滯,抑制乳腺癌的細胞增殖 (Yang et al., 2014a)。ASNS 在神經膠質瘤中高表達 (Panosyan et al., 2014)。ASNS 是卵巢癌的潛在生物標誌物 (Lorenzi et al., 2006; Lorenzi et al., 2008; Lorenzi and Weinstein, 2009)。ASNS encodes asparagine synthase. The ASNS gene complements the temperature-sensitive hamster mutation ts11, which blocks progression to the G1 phase of the cell cycle at non-permissive temperatures (RefSeq, 2002). ASNS expression is induced by glucose deprivation and protects pancreatic cancer cells from apoptosis (Cui et al., 2007). ASNS is associated with drug resistance in leukemia and uterine cancer (Lin et al., 2012; Zhang et al., 2013a). ASNS knockdown in A375 cells down-regulated the expression levels of CDK4, CDK6 and cyclin D1 and up-regulated the expression of p21 (Li et al., 2015a). Downregulation of ASNS induces cell cycle arrest and inhibits cell proliferation in breast cancer (Yang et al., 2014a). ASNS is highly expressed in gliomas (Panosyan et al., 2014). ASNS is a potential biomarker for ovarian cancer (Lorenzi et al., 2006; Lorenzi et al., 2008; Lorenzi and Weinstein, 2009).
ATP5F1 編碼 ATP 合成酶,H + 轉運,線粒體 Fo 複合物,亞基 B1,這是線粒體 ATP 合成酶的亞基 (RefSeq, 2002)。ATP5F1 在乙型肝炎病毒相關肝細胞癌中上調 (Lee et al., 2008a)。ATP5F1 encodes ATP synthase, H+ transport, mitochondrial Fo complex, subunit B1, which is the subunit of mitochondrial ATP synthase (RefSeq, 2002). ATP5F1 is upregulated in hepatitis B virus-associated hepatocellular carcinoma (Lee et al., 2008a).
BMS1 編碼 BMS1 核糖體生物合成因數,位於染色體 10q11.21上。酵母中的一種類似蛋白在 35S-rRNA 加工中發揮功能,其中包括一系列對於 40S 核糖體形成關鍵的分裂步驟 (RefSeq, 2002; Perez-Fernandez et al., 2011)。BMS1 encodes the BMS1 ribosomal biosynthesis factor and is located on chromosome 10q11.21. A similar protein in yeast functions in 35S-rRNA processing, which includes a series of cleavage steps critical for 40S ribosome formation (RefSeq, 2002; Perez-Fernandez et al., 2011).
BMS1P5 編碼 BMS1 核糖體生物合成假因數 5,位於染色體 10q11.22上 (RefSeq, 2002)。BMS1P5 encodes BMS1
BRK1(也稱為 C3orf10 或 HSPC300)編碼 Wave 複合體的最小亞基,是胚胎發育和細胞轉化過程中參與肌動蛋白細胞骨架動力學的 Wave/Scar 途徑的重要調節基因 (Derivery et al., 2008; Escobar et al., 2010)。BRK1 在不同癌症類型中均具有致癌可能性,包括肺癌和腎細胞癌 (Cascon et al., 2007; Cai et al., 2009; Escobar et al., 2010)。BRK1 由轉錄因子 Sp1 及 NRF-1 調節。它參與 Arp2/3 調節之後的 Wave/Scar 途徑,是細胞增殖和轉化需要的 (Li et al., 2014a; van't Veer et al., 2006; Escobar et al., 2010; Wang et al., 2013c)。BRK1 (also known as C3orf10 or HSPC300) encodes the smallest subunit of the Wave complex and is an important regulator of the Wave/Scar pathway involved in actin cytoskeleton dynamics during embryonic development and cellular transformation (Derivery et al., 2008 ; Escobar et al., 2010). BRK1 has oncogenic potential in different cancer types, including lung cancer and renal cell carcinoma (Cascon et al., 2007; Cai et al., 2009; Escobar et al., 2010). BRK1 is regulated by the transcription factors Sp1 and NRF-1. It is involved in the Wave/Scar pathway after Arp2/3 regulation and is required for cell proliferation and transformation (Li et al., 2014a; van't Veer et al., 2006; Escobar et al., 2010; Wang et al., 2013c).
BTBD1 編碼含 BTB (POZ) 結構域蛋白 1。該蛋白的 C 末端結合拓撲異構酶 I。N-末端包含脯氨酸富含區域和 BTB/POZ 結構域,這兩者通常參與蛋白-蛋白的相互作用 (RefSeq, 2002)。BTBD1 encodes BTB (POZ) domain-containing
BUB1B 編碼參與紡錘體步驟功能的激酶。該蛋白位於著絲點,在細胞分裂後期促進複合體/細胞週期體 (APC/C) 的抑制中發揮作用,從而延緩細胞分裂後期的發作並確保正確的染色體分離。受損紡錘體檢驗點存在於許多類型的癌症中 (RefSeq, 2002)。BUB1B 是一種腫瘤抑制蛋白。BUB1B 調節紡錘體裝配步驟。BUB1B 在腫瘤中失活或下調。BUB1B 基因突變也與腫瘤的發展相關 (Aylon and Oren, 2011; Fagin, 2002; Malumbres and Barbacid, 2007; Rao et al., 2009)。BUB1B 透過啟動癌基因而與胃癌發生有關 (Resende et al., 2010)。BUB1B 突變是結直腸癌的原因之一 (Karess et al., 2013; Grady, 2004)。BUB1B encodes a kinase involved in spindle step function. Located at the centromere, this protein plays a role in the repression of the anaphase-promoting complex/cell cycle body (APC/C), which delays the onset of anaphase and ensures correct chromosome segregation. Damaged spindle checkpoints are present in many types of cancer (RefSeq, 2002). BUB1B is a tumor suppressor protein. BUB1B regulates the spindle assembly step. BUB1B is inactivated or downregulated in tumors. Mutations in the BUB1B gene are also associated with tumor development (Aylon and Oren, 2011; Fagin, 2002; Malumbres and Barbacid, 2007; Rao et al., 2009). BUB1B has been implicated in gastric carcinogenesis by initiating oncogenes (Resende et al., 2010). BUB1B mutations are one of the causes of colorectal cancer (Karess et al., 2013; Grady, 2004).
C11orf70 編碼具有未表徵功能的蛋白,但與導致肌萎縮性側索硬化的突變蛋白相關 (Wang et al., 2015i)。相比于正常睾丸組織,C11orf70 在睾丸生殖細胞腫瘤中下調 (Gonzalez-Exposito et al., 2015; Alagaratnam et al., 2009)。口腔鱗狀細胞癌中 C11orf70 的遺傳區域顯示DNA拷貝數畸變,這與口腔癌特定的死亡率相關 (Chen et al., 2015a)。C11orf70 encodes a protein with an uncharacterized function, but is associated with a mutant protein that causes amyotrophic lateral sclerosis (Wang et al., 2015i). C11orf70 is downregulated in testicular germ cell tumors compared to normal testicular tissue (Gonzalez-Expposito et al., 2015; Alagaratnam et al., 2009). The genetic region of C11orf70 in oral squamous cell carcinoma shows DNA copy number aberrations, which are associated with oral cancer-specific mortality (Chen et al., 2015a).
C11orf80 編碼染色體 11 開放閱讀框 80,位於染色體 11q13.2 上 (RefSeq, 2002)。C11orf80 encodes the chromosome 11
C1orf198 編碼染色體 1 開放閱讀框 198,位於染色體 1q42.2 上 (RefSeq, 2002)。C1orf198 encodes open reading frame 198 of
C20orf24 編碼染色體 20 開放閱讀框 24,位於染色體 20q11.23 上 (RefSeq, 2002)。C20orf24 在從腺瘤到癌症的染色體不穩定相關進展中起重要作用。與腺瘤相比,C20orf24 在癌症中顯著過度表達。C20orf24 可作為結直腸癌的一種高特異性生物標誌物 (Carvalho et al., 2009)。C20orf24 encodes open reading frame 24 of
CAD 編碼三功能蛋白質氨甲醯合成酶 2、天門冬氨酸轉移酶和二氫乳清酸酶,其催化嘧啶生物合成途徑的前三次反應 (RefSeq, 2002)。CAD 活性在不同癌症類型中增加,包括肝細胞瘤、肉瘤、腎腺癌,並且非常頻繁地與 CAD 基因的擴增有關 (Smith et al., 1990; Aoki and Weber, 1981; Smith et al., 1997)。CAD 是不同癌基因和腫瘤生成的靶標,其調節 MAPK、mTORC1 和 c-Myc 等通路 (Mac and Farnham, 2000; Graves et al., 2000; Sharma et al., 2014)。CAD 促進雄激素受體易位進入細胞核並刺激攝護腺腫瘤細胞的轉錄活性。攝護腺癌根治術後,較高的 CAD mRNA 水準與腫瘤局部擴大和癌症復發有關 (Morin et al., 2012)。CAD encodes the trifunctional proteins carbamate synthase 2, aspartate transferase and dihydroorotase, which catalyze the first three reactions of the pyrimidine biosynthetic pathway (RefSeq, 2002). CAD activity is increased in different cancer types, including hepatoma, sarcoma, renal adenocarcinoma, and is very frequently associated with amplification of the CAD gene (Smith et al., 1990; Aoki and Weber, 1981; Smith et al., 1997). CAD is a target of diverse oncogenes and tumorigenesis that regulates pathways such as MAPK, mTORC1 and c-Myc (Mac and Farnham, 2000; Graves et al., 2000; Sharma et al., 2014). CAD promotes androgen receptor translocation into the nucleus and stimulates transcriptional activity in prostate tumor cells. After radical prostatectomy, higher CAD mRNA levels are associated with local tumor expansion and cancer recurrence (Morin et al., 2012).
CARM1 編碼共啟動因數相關精氨酸甲基轉移酶 1。CARM1 屬於蛋白質精氨酸甲基轉移酶 (PRMT) 家族。所編碼的酶催化蛋白質精氨醯殘基的胍基氮的甲基化。所述酶參與基因表達 (RefSeq, 2002)。CARM1 已經表明在結直腸癌和攝護腺癌、黑色素瘤和乳腺癌中失調。CARM1 不僅在攝護腺腫瘤中而且也在攝護腺上皮內瘤 (PIN) 中過度表達。CARM1 在非小細胞肺癌 (NSCLC) 中顯著過度表達。肝細胞癌變過程中,CARM1 表達在腺瘤中升高,在癌症中異常 (Limm et al., 2013; Osada et al., 2013; Elakoum et al., 2014; Baldwin et al., 2014)。CARM1 甲基化染色質重塑因子 BAF155,以增強腫瘤進展和轉移 (Wang et al., 2014a; Stefansson and Esteller, 2014)。CARM1 encodes co-initiation factor-related
CCNA2 編碼細胞週期蛋白 A2,這是高度保守的細胞週期蛋白家族的一員。CCNA2 結合和啟動 CDC2 或 CDK2 激酶,從而促進細胞週期 G1/S 和 G2/M 過渡 (RefSeq, 2002)。CCNA2 的過度表達抑制肝細胞癌細胞的增殖。CCNA2 在子宮內膜腺癌細胞中的過度表達降低細胞生長並增加細胞凋亡。CCNA2 在黑色素瘤細胞中的過度表達降低腫瘤生長和轉移,同時增加腫瘤細胞凋亡 (Lau, 2011)。CCNA2 可促進癌細胞增殖、侵襲、黏附、分化、存活和轉移。它在血管生成和細胞外基質的產生中起著重要作用。當在胃癌細胞中過度表達時,CCNA2 促進腫瘤生長並增加腫瘤血管形成。CCNA2 的沉寂降低胰腺癌細胞的腫瘤生長。CCNA2 可促進攝護腺癌細胞的增殖 (Lau, 2011; Chen and Du, 2007)。CCNA2 過度表達誘導上皮-間質轉化,導致咽喉腫瘤的侵襲和轉移 (Liu et al., 2015e)。CCNA2 在結直腸癌失調 (Chang et al., 2014)。CCNA2 在攝護腺癌、神經膠質瘤、胰腺癌和乳腺癌中過度表達。CCNA2 與乳腺癌的侵襲性增加、血管化和雌激素非依賴性相關,這表明 CCNA2 在乳腺癌進展中的主要作用 (Zuo et al., 2010)。CCNA2 encodes cyclin A2, a member of the highly conserved cyclin family. CCNA2 binds and initiates CDC2 or CDK2 kinases, thereby promoting cell cycle G1/S and G2/M transitions (RefSeq, 2002). Overexpression of CCNA2 inhibits the proliferation of hepatocellular carcinoma cells. Overexpression of CCNA2 in endometrial adenocarcinoma cells reduces cell growth and increases apoptosis. Overexpression of CCNA2 in melanoma cells reduces tumor growth and metastasis while increasing tumor cell apoptosis (Lau, 2011). CCNA2 promotes cancer cell proliferation, invasion, adhesion, differentiation, survival and metastasis. It plays an important role in angiogenesis and the production of extracellular matrix. When overexpressed in gastric cancer cells, CCNA2 promoted tumor growth and increased tumor angiogenesis. Silencing of CCNA2 reduces tumor growth in pancreatic cancer cells. CCNA2 promotes the proliferation of prostate cancer cells (Lau, 2011; Chen and Du, 2007). Overexpression of CCNA2 induces epithelial-mesenchymal transition, leading to the invasion and metastasis of throat tumors (Liu et al., 2015e). CCNA2 is dysregulated in colorectal cancer (Chang et al., 2014). CCNA2 is overexpressed in prostate cancer, glioma, pancreatic cancer and breast cancer. CCNA2 is associated with increased aggressiveness, vascularization, and estrogen independence in breast cancer, suggesting a major role for CCNA2 in breast cancer progression (Zuo et al., 2010).
CCND1 編碼細胞週期蛋白 D1。 它屬高度保守的細胞週期蛋白家族,其成員的特點是在整個細胞週期中都富含蛋白。改變細胞週期進程的 CCND1 之突變、擴增和過度表達經常可在各種腫瘤中觀察到,並可能有助於腫瘤癌變 (RefSeq, 2002)。CCND1 在口腔鱗狀細胞癌、胃腸間質瘤、非小細胞肺癌、垂體瘤與乳腺癌淋巴結轉移患者中擴增和過度表達 (Noorlag et al., 2015; Dworakowska, 2005; Gautschi et al., 2007; Lambros et al., 2007; Yang et al., 2008; Yu and Melmed, 2001)。CCND1 在套細胞淋巴瘤、胰腺神經內分泌腫瘤、甲狀旁腺腺瘤和尤因肉瘤中過度表達 (Navarro et al., 2011; Sander, 2011; Capurso et al., 2012; Delas et al., 2013; Setoodeh et al., 2013; Sanchez et al., 2008; Westin et al., 2009)。CCND1 可增加結直腸癌的風險 (Yang et al., 2012b; Andersen et al., 2013)。CCND1 基因改變可導致膀胱癌 (Zhang et al., 2003; Baffa et al., 2006)。CCND1 encodes cyclin D1. It belongs to a family of highly conserved cyclins whose members are characterized by protein enrichment throughout the cell cycle. Mutation, amplification and overexpression of CCND1 that alter cell cycle progression are frequently observed in various tumors and may contribute to tumor carcinogenesis (RefSeq, 2002). CCND1 is amplified and overexpressed in patients with oral squamous cell carcinoma, gastrointestinal stromal tumor, non-small cell lung cancer, pituitary tumor, and breast cancer with lymph node metastases (Noorlag et al., 2015; Dworakowska, 2005; Gautschi et al., 2007 ; Lambros et al., 2007; Yang et al., 2008; Yu and Melmed, 2001). CCND1 is overexpressed in mantle cell lymphoma, pancreatic neuroendocrine tumor, parathyroid adenoma, and Ewing's sarcoma (Navarro et al., 2011; Sander, 2011; Capurso et al., 2012; Delas et al., 2013 ; Setoodeh et al., 2013; Sanchez et al., 2008; Westin et al., 2009). CCND1 increases the risk of colorectal cancer (Yang et al., 2012b; Andersen et al., 2013). Alterations in the CCND1 gene can lead to bladder cancer (Zhang et al., 2003; Baffa et al., 2006).
CCT3 編碼含 TCP1 伴護蛋白,亞基 3 (γ),一種分子伴護子 (RefSeq, 2002)。CCT3 在肝細胞癌中升高 (Midorikawa et al., 2002; Skawran et al., 2008)。CCT3 是卵巢癌的一種潛在新穎的生物標誌物 (Peters et al., 2005)。CCT3 encodes a TCP1-containing chaperone, subunit 3 (γ), a molecular chaperone (RefSeq, 2002). CCT3 is elevated in hepatocellular carcinoma (Midorikawa et al., 2002; Skawran et al., 2008). CCT3 is a potentially novel biomarker for ovarian cancer (Peters et al., 2005).
CCT4 編碼含 TCP1 伴護蛋白,亞基 4。透過多輪 ATP 驅動的釋放和重新結合部分折疊的中間形式,CCT4 輔助新翻譯多肽底物的折疊 (RefSeq, 2002)。CCT4 失調形成食管鱗狀細胞癌和肺腺癌 (Wang et al., 2015j; Tano et al., 2010)。CCT4 在胃癌中上調 (Malta-Vacas et al., 2009)。CCT4 encodes a TCP1-containing chaperone, subunit 4. CCT4 assists in the folding of newly translated polypeptide substrates through multiple rounds of ATP-driven release and reassociation of a partially folded intermediate form (RefSeq, 2002). Dysregulation of CCT4 leads to esophageal squamous cell carcinoma and lung adenocarcinoma (Wang et al., 2015j; Tano et al., 2010). CCT4 is upregulated in gastric cancer (Malta-Vacas et al., 2009).
CDC27 編碼細胞分裂週期 27。由該基因編碼的蛋白質是後期促進複合體 (APC) 的一個元件。該蛋白可能參與有絲分裂時點的控制 (RefSeq, 2002)。CDC27 在下調時,增加三陰性乳腺癌細胞和鱗狀細胞宮頸癌的放射抵抗性 (Rajkumar et al., 2005; Ren et al., 2015)。 CDC27 在肝細胞癌的進展中起著至關重要的作用,並與食管鱗狀細胞癌和胰腺癌預後較差相關 (Ahn et al., 2014; Wang et al., 2015h)。CDC27 多態性可能透過影響細胞的有絲分裂進程而有助於乳腺癌的易感性形成 (Guo et al., 2015)。CDC27 突變牽涉攝護腺癌 (Lindberg et al., 2013)。 CDC27 突變和下調牽涉幾個乳腺癌和結腸癌細胞系 (Fan et al., 2004; Roy et al., 2010; Pawar et al., 2010)。CDC27 encodes cell division cycle 27. The protein encoded by this gene is an element of the anaphase-promoting complex (APC). This protein may be involved in the control of mitotic timing (RefSeq, 2002). CDC27, when downregulated, increases radioresistance in triple-negative breast cancer cells and squamous cell cervical cancer (Rajkumar et al., 2005; Ren et al., 2015). CDC27 plays a crucial role in the progression of hepatocellular carcinoma and is associated with poor prognosis in esophageal squamous cell carcinoma and pancreatic cancer (Ahn et al., 2014; Wang et al., 2015h). CDC27 polymorphisms may contribute to breast cancer susceptibility by affecting mitotic progression in cells (Guo et al., 2015). CDC27 mutations have been implicated in prostate cancer (Lindberg et al., 2013). CDC27 mutation and downregulation have been implicated in several breast and colon cancer cell lines (Fan et al., 2004; Roy et al., 2010; Pawar et al., 2010).
CDK12 編碼細胞週期蛋白依賴性激酶 12,位於染色體 17q12上 (RefSeq, 2002)。CDK12 突變在多種腫瘤中發現,包括卵巢癌、乳腺癌、攝護腺癌和腸道腫瘤 (Vrabel et al., 2014)。CDK12 encodes cyclin-
CDK13 編碼細胞週期蛋白依賴性激酶 13,其是細胞週期蛋白依賴性絲氨酸/蘇氨酸蛋白激酶家族的一員。已知本家族的成員在細胞週期調控的主開關中起著重要作用。它們可能在 mRNA 加工中起作用,並可能參與造血作用的調節 (RefSeq, 2002)。CDK13 與胰腺癌和皮膚癌有關 (Ansari et al., 2015; Nelson et al., 1999; Chandramouli et al., 2007)。CDK13 在肝細胞癌中擴增 (Kim et al., 2012b)。CDK13 encodes cyclin-dependent kinase 13, a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family are known to play important roles in the master switch of cell cycle regulation. They may have a role in mRNA processing and may be involved in the regulation of hematopoiesis (RefSeq, 2002). CDK13 has been implicated in pancreatic and skin cancers (Ansari et al., 2015; Nelson et al., 1999; Chandramouli et al., 2007). CDK13 is amplified in hepatocellular carcinoma (Kim et al., 2012b).
CDK2 編碼細胞週期蛋白依賴性激酶 2,即參與細胞週期調控的絲氨酸/蘇氨酸蛋白激酶。該蛋白質的活性在 G1 向 S 期轉變期間尤為重要 (RefSeq, 2002)。CDK2 過度表達提示細胞週期調節異常,這與癌細胞過度增殖直接相關 (Chohan et al., 2015)。CDK2 與白血病、結直腸癌、黑色素瘤、人乳頭狀瘤病毒相關宮頸瘤、肺癌、乳腺癌和攝護腺癌有關 (Foster et al., 2001; Zajac-Kaye, 2001; Raso et al., 2013; He et al., 2013; Duensing and Munger, 2002; Hu and Zuckerman, 2014; Agarwal, 2000)。CDK2 在套細胞淋巴瘤中高表達 (Rummel et al., 2004)。CDK2 encodes cyclin-dependent kinase 2, a serine/threonine protein kinase involved in cell cycle regulation. The activity of this protein is particularly important during the transition from G1 to S phase (RefSeq, 2002). Overexpression of CDK2 suggests dysregulation of the cell cycle, which is directly associated with excessive cancer cell proliferation (Chohan et al., 2015). CDK2 has been implicated in leukemia, colorectal cancer, melanoma, human papillomavirus-associated cervical, lung, breast, and prostate cancer (Foster et al., 2001; Zajac-Kaye, 2001; Raso et al., 2013 ; He et al., 2013; Duensing and Munger, 2002; Hu and Zuckerman, 2014; Agarwal, 2000). CDK2 is highly expressed in mantle cell lymphoma (Rummel et al., 2004).
CDK5RAP3 編碼 CDK5 調節亞基相關蛋白 3。CDK5RAP3 在負責轉錄調控和細胞週期進程的信號途徑中起作用。它可能在腫瘤發生和轉移中起作用 (RefSeq, 2002)。CDK5RAP3 在肝細胞癌中過度表達並促進轉移 (Mak et al., 2011; Mak et al., 2012)。CDK5RAP3 encodes CDK5 regulatory subunit-associated
CDK7 編碼細胞週期蛋白依賴性激酶 7,其是細胞週期蛋白依賴性蛋白激酶家族的一員。它是轉錄因子 TFIIH(其參與轉錄啟動和 DNA 修復)的一個重要組成部分。該蛋白質被認為可作為轉錄調節和細胞週期之間的直接聯系 (RefSeq, 2002)。 CDK7 基因多態性可讓患者透過基因-環境或基因-基因相互作用而罹患乳腺癌 (Yoo and Kang, 2003)。CDK7 與胰腺癌風險增加有關 (Efthimiou et al., 2001)。CDK7 與乳腺癌有關 (Cance and Liu, 1995)。CDK7 encodes cyclin-dependent kinase 7, a member of the cyclin-dependent protein kinase family. It is an important component of the transcription factor TFIIH, which is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between transcriptional regulation and the cell cycle (RefSeq, 2002). CDK7 gene polymorphisms can predispose patients to breast cancer through gene-environment or gene-gene interactions (Yoo and Kang, 2003). CDK7 is associated with an increased risk of pancreatic cancer (Efthimiou et al., 2001). CDK7 has been implicated in breast cancer (Cance and Liu, 1995).
CDK9 編碼細胞週期蛋白依賴性激酶 9,其是細胞週期蛋白依賴性蛋白激酶家族的一員。該蛋白質形成一種複合體,由其亞基細胞週期蛋白 T 或細胞週期蛋白 K 調節 (RefSeq, 2002)。CDK9 似乎參與幾種細胞類型的分化程序,如肌細胞、單核細胞和神經元。CDK9 似乎在單核細胞中具有抗凋亡作用。CDK9 在細胞的幾個生理過程的參與可能導致癌症發生 (De and Giordano, 2002)。CDK9 encodes cyclin-dependent kinase 9, which is a member of the cyclin-dependent protein kinase family. This protein forms a complex that is regulated by its subunits cyclin T or cyclin K (RefSeq, 2002). CDK9 appears to be involved in the differentiation program of several cell types, such as myocytes, monocytes, and neurons. CDK9 appears to have anti-apoptotic effects in monocytes. The involvement of CDK9 in several physiological processes in cells may lead to carcinogenesis (De and Giordano, 2002).
CELSR3 編碼鈣黏蛋白,EGF LAG 七通 G 型受體 3。所編碼的蛋白可能參與接觸依賴性神經突生長的調節,並且可能在腫瘤形成中起作用 (RefSeq, 2002)。微列陣篩查發現,與正常口腔黏膜相比,CELSR3 在原發口腔鱗狀細胞癌中超甲基化 (Khor et al., 2014)。CELSR3 與卵巢癌和腦腫瘤有關 (Asad et al., 2014; Katoh and Katoh, 2007)。CELSR3 在胰腺和肝腫瘤星狀細胞中上調 (Erkan et al., 2010)。CELSR3 encodes cadherin, EGF LAG seven-way G-
CEP97 編碼中心體蛋白 97kDa,位於染色體 3q12.3 上 (RefSeq, 2002)。CEP97 與乳腺癌有關 (Rappa et al., 2014)。CEP97 encodes a centrosome protein of 97 kDa located on chromosome 3q12.3 (RefSeq, 2002). CEP97 has been implicated in breast cancer (Rappa et al., 2014).
CFL1 編碼絲切蛋白 1。其參與從細胞質到細胞核的肌動蛋白-絲切蛋白複合體易位 (RefSeq, 2002)。CFL1 突變與多發性內分泌腫瘤類型 4 和膠質母細胞瘤相關 (Solomon et al., 2008; Georgitsi, 2010)。CFL1 在淋巴瘤、白血病、神經母細胞瘤、卵巢癌、攝護腺癌、乳腺癌、肺癌和間皮瘤中過度表達 (Rana et al., 2008)。CFL1 在睾丸生殖細胞腫瘤中下調 (von Eyben, 2004)。CFL1 encodes
CHD3 編碼染色質解旋酶 DNA 結合蛋白 3。該蛋白是一種稱為 Mi-2/NuRD 複合體的組蛋白脫乙醯基酶複合體的組分之一,其透過脫乙醯化組蛋白參與染色質重塑 (RefSeq, 2002)。CHD3 在胰腺上皮內瘤變和胰腺癌中上調 (Wang et al., 2011)。CHD3 突變與胃癌和結直腸癌有關 (Kim et al., 2011a)。CHD3 在急性髓細胞白血病中過度表達 (Camos et al., 2006)。CHD3 encodes the chromatin helicase DNA-binding
CHD4 編碼染色質解旋酶 DNA 結合蛋白 4。它代表了核小體重構和脫乙醯基酶複合體的主要成分,並在後生轉錄抑制中起著重要作用。該基因的體細胞突變與漿液性子宮內膜腫瘤有關 (RefSeq, 2002)。CHD4 是急性骨髓性白血病的新型治療靶標 (Sperlazza et al., 2015)。CHD4 從表觀遺傳學上在 EpCAM+ 肝癌幹細胞中控制基因調控以及 DNA 損傷應答 (Nio et al., 2015)。CHD4 調製 BRCA2 基因突變癌細胞的治療反應 (Guillemette et al., 2015)。CHD4 與膠質母細胞瘤和結腸癌有關 (Cai et al., 2014; Chudnovsky et al., 2014)。CHD4 encodes chromatin helicase DNA-binding protein 4. It represents a major component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Somatic mutations in this gene are associated with serous endometrial tumors (RefSeq, 2002). CHD4 is a novel therapeutic target for acute myeloid leukemia (Sperlazza et al., 2015). CHD4 epigenetically controls gene regulation and DNA damage response in EpCAM+ liver cancer stem cells (Nio et al., 2015). CHD4 modulates therapeutic response in BRCA2-mutated cancer cells (Guillemette et al., 2015). CHD4 has been implicated in glioblastoma and colon cancer (Cai et al., 2014; Chudnovsky et al., 2014).
CHD5 編碼染色質解旋酶 DNA 結合蛋白 5。CHD5 是一個潛在的腫瘤抑制因數,可能在神經母細胞瘤的發展中發揮作用 (RefSeq, 2002)。CHD5 作為神經膠質瘤和多種其他類型腫瘤(包括乳腺癌、結腸癌、肺癌、卵巢癌和攝護腺癌)的一種抑制基因 (Kolla et al., 2014)。CHD5 encodes the chromatin helicase DNA-binding
CIRH1A(也稱為 Cirhin)編碼肝硬化常染色體隱性 1 A,這是一種位於核仁的含蛋白的 WD40 重複蛋白。它會導致北美印第安人兒童肝硬化 (NAIC) (RefSeq, 2002)。CIRH1A 可上調標準 NF-κB元件,可能參與在含 NF-κB 元素的其他基因調控。這表明,CIRH1A 可影響癌症相關 NF-κB 通路 (Yu et al., 2009)。CIRH1A (also known as Cirhin) encodes cirrhotic autosomal recessive 1A, a protein-containing WD40 repeat protein located in the nucleolus. It causes cirrhosis in North American Indian children (NAIC) (RefSeq, 2002). CIRH1A upregulates standard NF-κB elements and may be involved in the regulation of other genes containing NF-κB elements. This suggests that CIRH1A can affect the cancer-associated NF-κB pathway (Yu et al., 2009).
COL1A1 編碼膠原蛋白,1 型,α1。1 型是存在於大多數結締組織中的纖維性膠原蛋白,在骨、角膜、真皮和肌腱中富含。染色體 17 和 22 之間(該基因和血小板衍生生長因數 β 基因所在位置)的相互易位與稱為隆突性皮膚纖維肉瘤的的特定皮膚腫瘤類型相關,其由生長因數未經調節的表達產生 (RefSeq, 2002)。COL1A1 在胃癌中差異性表達 (Yasui et al., 2004)。COL1A1 色素隆突性皮膚纖維肉瘤有關 (Zhang et al., 2013c)。COL1A1 encodes collagen,
COL1A2 編碼膠原蛋白,1 型,α2。1 型是存在於大多數結締組織中的纖維性膠原蛋白,在骨、角膜、真皮和肌腱中富含 (RefSeq, 2002)。COL1A2 與胃癌有關 (Yasui et al., 2004; Yasui et al., 2005)。COL1A2 encodes collagen,
COL6A1 編碼膠原蛋白,6 型,α1。膠原蛋白VI 是微纖維的主要結構成分。編碼膠原 VI 亞基的基因突變導致常染色體顯性遺傳疾病Bethlem肌病 (RefSeq, 2002)。COL6A1 在去勢抵抗攝護腺癌的反應基質中上調,促進腫瘤生長 (Zhu et al., 2015c)。COL6A1 在 CD166-胰腺癌細胞中過度表達,這些細胞比 CD166+ 癌細胞顯示出更強的侵襲和遷移活性 (Fujiwara et al., 2014)。COL6A1 在骨轉移癌中高表達 (Blanco et al., 2012)。COL6A1 被發現在宮頸癌和卵巢癌中上調 (Zhao et al., 2011; Parker et al., 2009)。COL6A1 在星形細胞瘤和膠質母細胞瘤中中差異性表達 (Fujita et al., 2008)。COL6A1 encodes collagen, type 6, alpha1. Collagen VI is the main structural component of microfibrils. Mutations in the gene encoding the collagen VI subunit cause the autosomal dominant disorder Bethlem myopathy (RefSeq, 2002). COL6A1 is upregulated in the reactive stroma of castration-resistant prostate cancer and promotes tumor growth (Zhu et al., 2015c). COL6A1 is overexpressed in CD166- pancreatic cancer cells, which show stronger invasive and migratory activities than CD166+ cancer cells (Fujiwara et al., 2014). COL6A1 is highly expressed in bone metastases (Blanco et al., 2012). COL6A1 was found to be upregulated in cervical and ovarian cancers (Zhao et al., 2011; Parker et al., 2009). COL6A1 is differentially expressed in astrocytomas and glioblastomas (Fujita et al., 2008).
COL6A3 編碼膠原蛋白、VI 型、α3,即 VI 型膠原蛋白的三種 α 鏈之一,這是在大多數結締組織中發現的一種珠狀絲膠原,對於基質組分組織很重要 (RefSeq, 2002)。COL6A3 編碼 VI 型膠原蛋白的 α-3 鏈,這是在大多數結締組織中發現的一種珠狀絲膠原,在基質組分的組織中起著重要作用 (RefSeq, 2002)。COL6A3 在結腸癌、膀胱癌和攝護腺癌中可變剪接。COL6A3 的長同種型幾乎在癌症樣本中特有表達,可潛在地作為新的癌症標誌物 (Thorsen et al., 2008)。 COL6A3 在胰腺導管腺癌組織中高度表達,並進行腫瘤特異性選擇性剪接 (Kang et al., 2014)。COL6A3 已被證明與高級別的卵巢癌相關,並有助於順鉑抗性的形成。COL6A3 被觀察到在胃癌組織中頻繁過度表達 (Xie et al., 2014)。COL6A3 突變可明顯預測結直腸癌患者具有更好的整體生存率,與腫瘤分化和 TNM 分期無關 (Yu et al., 2015b)。據報告,COL6A3 表達在胰腺癌、結腸癌、胃癌、黏液表皮樣癌和卵巢癌中增加。在結腸癌、膀胱癌、攝護腺癌和胰腺癌中檢測到包括外顯子 3、4 和 6 的癌症相關轉錄物變體 (Arafat et al., 2011; Smith et al., 2009; Yang et al., 2007; Xie et al., 2014; Leivo et al., 2005; Sherman-Baust et al., 2003; Gardina et al., 2006; Thorsen et al., 2008)。在卵巢癌中,COL6A3 水準與較高的腫瘤分級相關,在胰腺癌中,COL6A3 被證明可表現一種合適的診斷血清生物標誌物 (Sherman-Baust et al., 2003; Kang et al., 2014)。COL6A3 encodes collagen, type VI, α3, one of the three α chains of type VI collagen, a beaded filament collagen found in most connective tissues and important for matrix component organization (RefSeq, 2002) . COL6A3 encodes the alpha-3 chain of type VI collagen, a beaded filament collagen found in most connective tissues and plays an important role in the organization of matrix components (RefSeq, 2002). COL6A3 is alternatively spliced in colon, bladder and prostate cancer. The long isoform of COL6A3 is almost exclusively expressed in cancer samples and could potentially serve as a new cancer marker (Thorsen et al., 2008). COL6A3 is highly expressed in pancreatic ductal adenocarcinoma tissues and undergoes tumor-specific alternative splicing (Kang et al., 2014). COL6A3 has been shown to be associated with high-grade ovarian cancer and contribute to the development of cisplatin resistance. COL6A3 was observed to be frequently overexpressed in gastric cancer tissues (Xie et al., 2014). COL6A3 mutation significantly predicts better overall survival in patients with colorectal cancer, independent of tumor differentiation and TNM stage (Yu et al., 2015b). COL6A3 expression has been reported to be increased in pancreatic, colon, gastric, mucoepidermoid and ovarian cancers. Cancer-associated transcript
COPG1(也稱為 COPG)編碼套體素蛋白複合體 (COPI) 的 γ 亞基,其介導逆行運輸(從高爾基體返回至 ER)和高爾基體內運輸。COPG1 結合至 ARF-GAP (Waters et al., 1991; Watson et al., 2004)。COPG1 與患者年齡以及惡性腫瘤的較高等級以及神經膠質肉瘤的等級相關 (Coppola et al., 2014)。COPG1 被發現在肺癌和肺癌相關內皮細胞中大量表達 (Park et al., 2008)。COPG1 (also known as COPG) encodes the gamma subunit of the set of voxel protein complex (COPI), which mediates retrograde transport (return from the Golgi to the ER) and intra-Golgi transport. COPG1 binds to ARF-GAP (Waters et al., 1991; Watson et al., 2004). COPG1 is associated with patient age as well as higher grade of malignancy and grade of gliosarcoma (Coppola et al., 2014). COPG1 was found to be abundantly expressed in lung cancer and lung cancer-associated endothelial cells (Park et al., 2008).
CREB3L1 編碼 cAMP 反應元件結合蛋白3 樣 1。為了回應 ER 應激,CREB3L1 被裂解,釋放的胞質轉錄因子結構域易位至細胞核。在那裏,它透過結合至框-B 元件啟動靶基因的轉錄 (RefSeq, 2002)。CREB3L1 突變經常發現於硬化性上皮樣纖維肉瘤 (SEF) (Prieto-Granada et al., 2015)。CREB3L1 由人類神經膠質瘤細胞系中的 ER 應激誘導,促進未折疊蛋白應答、細胞外基質產生和細胞遷移 (Vellanki et al., 2013)。CREB3L1 在膀胱癌中從表觀遺傳學上沉寂,促進腫瘤細胞的擴散和遷移 (Rose et al., 2014)。CREB3L1 在乳腺癌的抑制腫瘤發生中起著重要作用。表達損失是出現轉移性表型所需的 (Mellor et al., 2013)。CREB3L1 encodes cAMP response element binding protein 3-like 1. In response to ER stress, CREB3L1 is cleaved and the released cytoplasmic transcription factor domain is translocated to the nucleus. There, it initiates transcription of target genes by binding to box-B elements (RefSeq, 2002). CREB3L1 mutations are frequently found in sclerosing epithelioid fibrosarcoma (SEF) (Prieto-Granada et al., 2015). CREB3L1 is induced by ER stress in human glioma cell lines, promoting unfolded protein responses, extracellular matrix production and cell migration (Vellanki et al., 2013). CREB3L1 is epigenetically silenced in bladder cancer, promoting tumor cell spread and migration (Rose et al., 2014). CREB3L1 plays an important role in suppressing tumorigenesis in breast cancer. Loss of expression is required for the emergence of a metastatic phenotype (Mellor et al., 2013).
CSTF1 編碼裂解刺激因數,3' 前 RNA,亞基 1,50kDa。它參與前 mRNA 的多聚腺苷酸化和 3' 端部裂解 (RefSeq, 2002)。CSTF1 變異被發現與 BRCA2 突變攜帶者的乳腺癌風險相關 (Blanco et al., 2015)。CSTF1 encodes a cleavage stimulus factor, 3' pre-RNA,
CTHRC1 編碼含膠原三股螺旋重複蛋白 1。CTHRC1 可能透過參與血管重構對動脈損傷的細胞反應中可能發揮作用。這個位點突變與 Barrett 食管和食管腺癌相關 (RefSeq, 2002)。 CTHRC1 顯示在胃癌和乳腺導管癌中表達增加 (Kim et al., 2013b; Yu et al., 2015a; Song et al., 2015)。CTHRC1 在結直腸癌中上調 (Yan et al., 2015a; Yan et al., 2015b)。CTHRC1 表達在感染乙肝病毒患者的肝細胞癌進展高度相關。CTHRC1 增強集落形成、遷移和肝癌細胞的侵襲 (Tameda et al., 2014; Zhang et al., 2015b)。CTHRC1 在非小細胞肺癌中過度表達。過度表達與腫瘤侵襲性和預後不良相關 (Ke et al., 2014b)。CTHRC1 在食管鱗狀細胞癌和 Barrett 腺癌中上調 (Timme et al., 2014)。CTHRC1 促進黑色素瘤的細胞黏附和存活 (Ip et al., 2011)。CTHRC1 encodes collagen-containing triple-
CXCL5 編碼趨化因數 C-X-C 基序配體 5。這種蛋白質擬結合 G 蛋白偶聯受體趨化因數 C-X-C 基序受體 2 以招募中性粒細胞,促進血管生成和重塑結締組織。該蛋白被認為在癌細胞增殖、遷移和侵襲中起作用 (RefSeq, 2002)。CXCL5 在腎細胞癌的存活、生長和轉移中發揮至關重要的作用 (Parihar and Tunuguntla, 2014)。CXCL5 參與食管癌和胃癌的慢性炎症過渡 (Verbeke et al., 2012)。CXCL5 與急性骨髓性白血病有關(Kittang et al., 2010)。CXCL5 encodes the chemokine
DCBLD2 編碼盤基蛋白、含 CUB 和 LCCL 結構域蛋白 2(也被稱為內皮細胞和平滑肌細胞來源的神經氈蛋白樣蛋白),這是一種跨膜共受體蛋白 (RefSeq, 2002)。DCBLD2 在膠質母細胞瘤和頭頸部癌症 (HNCS) 中上調,是 EGFR 刺激腫瘤發生所需要的 (Feng et al., 2014)。此外,DCBLD2 在高度轉移性肺癌亞系和組織樣本中上調 (Koshikawa et al., 2002)。與此相反,在胃癌中,DCBLD2 的表達透過其啟動子的甲基化而沉寂 (Kim et al., 2008)。DCBLD2 encodes discoidin, CUB and LCCL domain-containing protein 2 (also known as endothelial and smooth muscle cell-derived neuropilin-like protein), a transmembrane co-receptor protein (RefSeq, 2002). DCBLD2 is upregulated in glioblastoma and head and neck cancer (HNCS) and is required for EGFR-stimulated tumorigenesis (Feng et al., 2014). In addition, DCBLD2 is upregulated in highly metastatic lung cancer sublines and tissue samples (Koshikawa et al., 2002). In contrast, in gastric cancer, DCBLD2 expression is silenced through methylation of its promoter (Kim et al., 2008).
DDX43 編碼 DEAD (Asp-Glu-Ala-Asp) 框多肽 43。DDX43 是一種 ATP 依賴性 RNA 解旋酶,並呈現出腫瘤特異性表達 (RefSeq, 2002)。DDX43 在葡萄膜黑色素瘤細胞和急慢性髓細胞性白血病中過度表達 (Chen et al., 2011a; Lin et al., 2014b; Ambrosini et al., 2014)。DDX43 是乳腺癌預後的一種生物標誌物 (Wiese and Pajeva, 2014)。DDX43 在膠質瘤細胞系中表達 (Akiyama et al., 2014)。DDX43 encodes DEAD (Asp-Glu-Ala-Asp) box polypeptide 43. DDX43 is an ATP-dependent RNA helicase and exhibits tumor-specific expression (RefSeq, 2002). DDX43 is overexpressed in uveal melanoma cells and acute and chronic myeloid leukemia (Chen et al., 2011a; Lin et al., 2014b; Ambrosini et al., 2014). DDX43 is a biomarker for breast cancer prognosis (Wiese and Pajeva, 2014). DDX43 is expressed in glioma cell lines (Akiyama et al., 2014).
DDX53 編碼 DEAD (Asp-Glu-Ala-Asp) 框多肽 53。DDX53 包含在 DEAD 框解旋酶蛋白家族成員中發現的多個結構域 (RefSeq, 2002)。癌症/睾丸抗原 DDX53 透過 HDAC2 實施 p53 表達的負面調控,並產生對抗癌藥物的耐藥性 (Kim et al., 2010b)。miR-200B 和癌症/睾丸抗原 DDX53 形成回饋環路,以對微管靶向藥物調節癌細胞系的侵襲、致瘤和血管生成反應 (Kim et al., 2013c)。miR-217 和 DDX53 形成回饋環路,以透過 EGFR 和 HER2 調節對抗癌藥物的反應 (Kim et al., 2016)。DDX53 是子宮肌瘤中具備異常 DNA 低甲基化狀態的幾個基因之一 (Maekawa et al., 2011)。從 21 個 B 細胞和 4 個 T細胞惡性腫瘤中來源的細胞系中,觀察到了針對 DDX53 的廣泛 mRNA 表達譜 (Liggins et al., 2010)。DDX53 encodes DEAD (Asp-Glu-Ala-Asp) box polypeptide 53. DDX53 contains multiple domains found in members of the DEAD box helicase protein family (RefSeq, 2002). The cancer/testis antigen DDX53 negatively regulates p53 expression through HDAC2 and confer resistance to anticancer drugs (Kim et al., 2010b). miR-200B and the cancer/testis antigen DDX53 form a feedback loop to modulate the invasive, tumorigenic and angiogenic responses of cancer cell lines to microtubule-targeted drugs (Kim et al., 2013c). miR-217 and DDX53 form a feedback loop to modulate the response to anticancer drugs through EGFR and HER2 (Kim et al., 2016). DDX53 is one of several genes with abnormal DNA hypomethylation status in uterine fibroids (Maekawa et al., 2011). A broad mRNA expression profile for DDX53 was observed in 21 B-cell and 4 T-cell malignancies-derived cell lines (Liggins et al., 2010).
DNAJC7 編碼 DnaJ (HSP40) 同源物,亞家族 C,成員 7,DNAJ 熱休克蛋白 (HSP) 40 蛋白質家族的一員。該蛋白質以 ATP 依賴性方式結合伴護蛋白 HSP70 和 HSP90,可能充當共伴護蛋白 (RefSeq, 2002)。DNAJC7 透過阻斷 p53 和 MDM2 之間的複合體形成而增強了 p53 的穩定性和活性 (Kubo et al., 2013)。DNAJC7 encodes a DnaJ (HSP40) homologue, subfamily C, member 7, a member of the DNAJ heat shock protein (HSP) 40 protein family. This protein binds chaperones HSP70 and HSP90 in an ATP-dependent manner, possibly acting as a co-chaperone (RefSeq, 2002). DNAJC7 enhances p53 stability and activity by blocking complex formation between p53 and MDM2 (Kubo et al., 2013).
DPP9 編碼二肽基肽酶 9。DPP9 似乎參與其底物活性的調控,並與多種疾病(包括 2 型糖尿病、肥胖和癌症)相關聯 (RefSeq, 2002)。DPP9 在乳腺癌和卵巢癌中發揮著潛在作用 (Wilson and Abbott, 2012)。DPP9 在細胞存活和增殖途徑的調節中起著重要的信號傳導作用 (Yao et al., 2011)。DPP9 mRNA 水準在睾丸腫瘤中升高 (Yu et al., 2010)。DPP9 在腦膜瘤中過度表達 (Stremenova et al., 2010)。DPP9 encodes dipeptidyl peptidase 9. DPP9 appears to be involved in the regulation of its substrate activity and has been implicated in a variety of diseases including type 2 diabetes, obesity and cancer (RefSeq, 2002). DPP9 has a potential role in breast and ovarian cancer (Wilson and Abbott, 2012). DPP9 plays an important signaling role in the regulation of cell survival and proliferation pathways (Yao et al., 2011). DPP9 mRNA levels are elevated in testicular tumors (Yu et al., 2010). DPP9 is overexpressed in meningiomas (Stremenova et al., 2010).
DPYD(也稱為 DPD)編碼二氫嘧啶脫氫酶,是尿嘧啶和胸腺嘧啶分解代謝途徑中的嘧啶分解酶以及初始和限速因數。此基因的突變導致二氫嘧啶脫氫酶缺乏(胸腺嘧啶-尿嘧啶尿症相關嘧啶代謝錯誤)並導致接收 5-氟尿嘧啶化療的癌症患者的毒性風險增加 (RefSeq, 2002)。DPYD 表達水準可作為胃癌化療療效的預測因數 (Wan et al., 2016)。在接受基於氟尿嘧啶的輔助聯合化療治療的患者中,發現 DPYD 變體與 3 級或更高級別氟尿嘧啶相關的不良事件增加之間存在著顯著關聯性 (Cavalcante et al., 2015; Lee et al., 2016; Boige et al., 2016)。在結直腸癌中,DPYD 多態性與 KRAS 野生型表達之間存在著相關性 (Kleist et al., 2015)。在結直腸癌中,DPYD 基因表達的上調導致氟尿嘧啶毒性 (Chai et al., 2015; Falvella et al., 2015; van Staveren et al., 2015; Nakamura et al., 2015; Chen et al., 2015c; Hu et al., 2015b)。DPYD 的多態性表達可能在確定頭頸部癌、胰腺癌、食管鱗狀細胞癌、消化道癌、胃癌、肝細胞癌和結直腸癌患者的治療反應很重要 (Kim et al., 2015; Toffoli et al., 2015; Ishizuka et al., 2015; Baba et al., 2015; Launay et al., 2016; Kikuchi et al., 2015; Li et al., 2016; Shimamoto et al., 2016; Bai et al., 2015; Dhawan et al., 2016)。DPYD (also known as DPD) encodes a dihydropyrimidine dehydrogenase, a pyrimidine-degrading enzyme in the uracil and thymine catabolic pathways and an initial and rate-limiting factor. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency (a thymidine-uraciluria-related pyrimidine metabolism error) and lead to an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy (RefSeq, 2002). DPYD expression level can be used as a predictor of chemotherapy efficacy in gastric cancer (Wan et al., 2016). In patients treated with fluorouracil-based adjuvant combination chemotherapy, a significant association was found between DPYD variants and increased
DROSHA 是微小 RNA 生物合成中的兩個關鍵酶之一,在許多癌症中過量表達,包括胃腸道腫瘤、乳腺癌和宮頸癌,並且似乎增強增殖、集落形成和腫瘤細胞遷移 (Avery-Kiejda et al., 2014; Havens et al., 2014; Zhou et al., 2013)。DROSHA, one of two key enzymes in microRNA biosynthesis, is overexpressed in many cancers, including gastrointestinal tumors, breast cancer, and cervical cancer, and appears to enhance proliferation, colony formation, and tumor cell migration (Avery-Kiejda et al. ., 2014; Havens et al., 2014; Zhou et al., 2013).
DSEL 編碼硫酸皮膚素異構酶樣蛋白,位於染色體 18q22.1 上 (RefSeq, 2002)。DSE 是 DSEL 的重要旁系。DSE 是肝細胞癌和結直腸癌免疫治療的免疫原性靶標 (Mizukoshi et al., 2011; Sasatomi et al., 2002)。DSEL encodes a dermatan sulfate isomerase-like protein on chromosome 18q22.1 (RefSeq, 2002). DSE is an important collateral line of DSEL. DSE is an immunogenic target for immunotherapy in hepatocellular carcinoma and colorectal cancer (Mizukoshi et al., 2011; Sasatomi et al., 2002).
DST(也稱為大皰性類天皰瘡抗原 I (BPAG1) )編碼肌張力異常蛋白,這是黏附連接斑塊蛋白質的血小板溶素蛋白家族的一員。全長同工型沒有定義,但是,在神經和肌肉組織或上皮組織中表達幾種同工型,把神經中間絲固定至肌動蛋白細胞骨架或含角蛋白中間絲固定至半橋粒 (RefSeq, 2002; Bouameur et al., 2014; Li et al., 2007)。DST 可能與乳腺癌轉移有關 (Sun et al., 2006)。針對 DST 的自身抗體可在淋巴細胞性白血病和濾泡性淋巴瘤中發現到 (Aisa et al., 2005; Taintor et al., 2007)。在鼻咽癌中,DST 在 5-8F 細胞(高致瘤和轉移能力)中相較於 6-10B 細胞(具備致瘤能力但無轉移能力)上調 (Fang et al., 2005)。DST 在頭頸部鱗狀細胞癌中高表達 (Lin et al., 2004)。在副腫瘤性天皰瘡中存在針對 DST 的自身抗體,這與腫瘤相關 (Yong and Tey, 2013; Wang et al., 2005; Preisz and Karpati, 2007; Zhu and Zhang, 2007)。攝護腺癌中的 DST 表達與疾病進展呈強烈逆相關 (Vanaja et al., 2003)。抗 DST自身抗體是黑色素瘤診斷的一個有前景的標誌物 (Shimbo et al., 2010)。DST 可發現於惡病質癌症患者的尿液 (Skipworth et al., 2010)。DST 在肺腺癌和鱗狀細胞癌中差異表達 (McDoniels-Silvers et al., 2002)。DST 明顯上調,伴隨浸潤性細胞生長 (Herold-Mende et al., 2001)。DST (also known as bullous pemphigoid antigen I (BPAG1)) encodes dystonia, a member of the thrombolysin family of adhesion-junction plaque proteins. The full-length isoform is not defined, however, several isoforms are expressed in neural and muscle tissue or in epithelial tissue, anchoring neural intermediate filaments to the actin cytoskeleton or keratin-containing intermediate filaments to hemidesmosomes (RefSeq, 2002; Bouameur et al., 2014; Li et al., 2007). DST may be associated with breast cancer metastasis (Sun et al., 2006). Autoantibodies against DST have been found in lymphocytic leukemia and follicular lymphoma (Aisa et al., 2005; Taintor et al., 2007). In nasopharyngeal carcinoma, DST is upregulated in 5-8F cells (high tumorigenic and metastatic potential) compared to 6-10B cells (tumorigenic but not metastatic) (Fang et al., 2005). DST is highly expressed in head and neck squamous cell carcinoma (Lin et al., 2004). Autoantibodies against DST are present in paraneoplastic pemphigus, which is associated with tumors (Yong and Tey, 2013; Wang et al., 2005; Preisz and Karpati, 2007; Zhu and Zhang, 2007). DST expression in prostate cancer is strongly inversely correlated with disease progression (Vanaja et al., 2003). Anti-DST autoantibodies are a promising marker for the diagnosis of melanoma (Shimbo et al., 2010). DST can be found in the urine of cachectic cancer patients (Skipworth et al., 2010). DST is differentially expressed in lung adenocarcinoma and squamous cell carcinoma (McDoniels-Silvers et al., 2002). DST is markedly up-regulated with infiltrative cell growth (Herold-Mende et al., 2001).
DYNC1H1 編碼動力蛋白重鏈 1,它是沿微管逆行運輸的主馬達蛋白的一個亞基。整個外顯子測序研究發現胰腺內導管內乳頭狀黏液性腫瘤患者的 DYNC1H1 基因內有體細胞突變 (Furukawa et al., 2011)。DYNC1H1 encodes dynein
EIF3C 編碼真核翻譯起始因數 3,亞基 C,位於染色體 16p11.2 上 (RefSeq, 2002)。EIF3C 在人 U-87 MG 細胞中過度表達,並促進細胞增殖 (Hao et al., 2015)。EIF3C 在結腸癌中高表達 (Song et al., 2013)。EIF3C mRNA 在睾丸精原細胞瘤中過度表達 (Rothe et al., 2000)。EIF3C encodes eukaryotic
EIF3CL 編碼真核翻譯起始因數 3,亞基 C 樣蛋白。它位於染色體 16p11.2 上 (RefSeq, 2002)。EIF3CL encodes eukaryotic
EIF3E 編碼真核翻譯起始因數 3,亞基 E,位於染色體 8q22-q23 上 (RefSeq, 2002)。EIF3E 可能在口腔鱗狀細胞癌的癌變中起著一定的作用 (Yong et al., 2014)。EIF3E 是膠質母細胞瘤的增殖和存活所必需的 (Sesen et al., 2014)。EIF3E 在乳腺癌進展中具有致癌作用。EIF3E 表達降低導致乳腺上皮細胞從上皮至間質細胞轉化 (Gillis and Lewis, 2013; Grzmil et al., 2010)。EIF3E 表達水準在膀胱癌中顯著增加 (Chen et al., 2011b)。EIF3E 牽涉非小細胞肺癌 (Marchetti et al., 2001)。EIF3E encodes eukaryotic
EXT2 編碼骨疣蛋白糖基轉移酶 2,這是參與硫酸肝素生物合成鏈延伸步驟的二個糖基轉移酶之一。這種基因的突變導致 II 型多發性外生骨疣 (RefSeq, 2002)。EXT2 突變在軟骨肉瘤中發揮作用 (Samuel et al., 2014)。EXT2 突變引起多發性骨軟骨瘤徵候群 (Jochmann et al., 2014)。EXT2 突變引起遺傳性多發外生性骨疣,導致硫酸乙醯肝素缺乏 (Huegel et al., 2013)。EXT2 encodes osteoprotein glycosyltransferase 2, one of two glycosyltransferases involved in the chain elongation step of heparin sulfate biosynthesis. Mutations in this gene cause multiple exostoses type II (RefSeq, 2002). EXT2 mutations play a role in chondrosarcoma (Samuel et al., 2014). EXT2 mutations cause multiple osteochondroma syndrome (Jochmann et al., 2014). Mutations in EXT2 cause hereditary multiple exostoses, resulting in heparin sulfate deficiency (Huegel et al., 2013).
F2R(也稱為 PAR1)編碼凝血因數 II 凝血酶受體,這是一種參與血栓形成回應調節的跨膜受體 (RefSeq, 2002)。F2R 結合至 Etk/Bmx 的普列克底物蛋白同源 (PH) 結構域。F2R 變體(無法結合 PH 結構域)減少乳腺腫瘤以及絨毛外滋養細胞浸潤 (Kancharla et al., 2015)。F2R 被認為可透過促進腫瘤細胞的遷移、血管生成和宿主血管細胞互動,從而促進癌細胞的侵襲和轉移 (Wojtukiewicz et al., 2015)。F2R 下調導致癌細胞死亡 (Burns and Thevenin, 2015)。F2R 多態性與直腸癌患者的急性損傷有關(Zhang et al., 2015a)。F2R 與預後不良(特別是 ER 陰性乳腺癌患者)相關 (Lidfeldt et al., 2015)。F2R 缺乏的小鼠顯示結腸腺癌生長下降 (Adams et al., 2015)。基質金屬蛋白酶 (MMP) -1 啟動 F2R 誘導血管生成 (Fan et al., 2015)。 F2R 參與了肺癌的 PTEN 下調 (Xu et al., 2015)。F2R 啟動誘導與上皮間質轉變相關的 Hippo-YAP 通路 (Jia et al., 2015; Owens et al., 2015; Yang et al., 2015a; Fujimoto et al., 2015)。F2R 啟動抑制降低 HER-2 陰性乳腺癌、肝細胞癌和胃癌的癌細胞遷移和侵襲 (Mussbach et al., 2015; Wang et al., 2015g; Gonda et al., 2015)。F2R (also known as PAR1) encodes the factor II thrombin receptor, a transmembrane receptor involved in the regulation of the thrombotic response (RefSeq, 2002). The F2R binds to the plectrin homology (PH) domain of Etk/Bmx. F2R variants (incapable of binding the PH domain) reduce mammary tumors as well as extravillous trophoblastic infiltration (Kancharla et al., 2015). F2Rs are thought to promote cancer cell invasion and metastasis by promoting tumor cell migration, angiogenesis, and host vascular cell interactions (Wojtukiewicz et al., 2015). Downregulation of F2R leads to cancer cell death (Burns and Thevenin, 2015). F2R polymorphisms are associated with acute injury in patients with rectal cancer (Zhang et al., 2015a). F2R is associated with poor prognosis, especially in patients with ER-negative breast cancer (Lidfeldt et al., 2015). F2R-deficient mice show decreased colon adenocarcinoma growth (Adams et al., 2015). Matrix metalloproteinase (MMP)-1 initiates F2R-induced angiogenesis (Fan et al., 2015). F2R is involved in PTEN downregulation in lung cancer (Xu et al., 2015). F2R priming induces the Hippo-YAP pathway associated with epithelial-mesenchymal transition (Jia et al., 2015; Owens et al., 2015; Yang et al., 2015a; Fujimoto et al., 2015). F2R priming inhibition reduces cancer cell migration and invasion in HER-2-negative breast, hepatocellular, and gastric cancers (Mussbach et al., 2015; Wang et al., 2015g; Gonda et al., 2015).
FADS2 編碼脂肪酸去飽和酶 2,這是脂肪酸去飽和酶基因家族的一員。去飽和酶透過引入脂肪醯基鏈定義碳之間的雙鍵來調節脂肪酸的不飽和度 (RefSeq, 2002)。FADS2 在肝細胞癌中上調 (Muir et al., 2013)。FADS2 活性在乳腺癌組織中增加 (Pender-Cudlip et al., 2013)。FADS2 表達與乳腺癌侵襲性有關 (Lane et al., 2003)。FADS2 抑制阻礙腸腫瘤發生 (Hansen-Petrik et al., 2002)。FADS2 encodes fatty acid desaturase 2, a member of the fatty acid desaturase gene family. Desaturases regulate the unsaturation of fatty acids by introducing double bonds between defined carbons of the fatty acyl chain (RefSeq, 2002). FADS2 is upregulated in hepatocellular carcinoma (Muir et al., 2013). FADS2 activity is increased in breast cancer tissues (Pender-Cudlip et al., 2013). FADS2 expression is associated with breast cancer aggressiveness (Lane et al., 2003). FADS2 inhibition hinders intestinal tumorigenesis (Hansen-Petrik et al., 2002).
FADS2 編碼脂肪酸去飽和酶 3。去飽和酶透過引入脂肪醯基鏈定義碳之間的雙鍵來調節脂肪酸的不飽和度 (RefSeq, 2002)。FADS2 encodes
FAM83D 編碼具有序列相似性的家族 83,成員 D,位於染色體 20q11.23上 (RefSeq, 2002)。FAM83D 的上調影響肝細胞癌細胞的增殖和侵襲 (Wang et al., 2015a; Liao et al., 2015)。FAM83D 在乳腺癌細胞系和原發性人類乳腺癌中顯著升高 (Wang et al., 2013e)。FAM83D encodes family 83 with sequence similarity, member D, on chromosome 20q11.23 (RefSeq, 2002). Upregulation of FAM83D affects the proliferation and invasion of hepatocellular carcinoma cells (Wang et al., 2015a; Liao et al., 2015). FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers (Wang et al., 2013e).
FN1 編碼纖連蛋白 1,這是一種糖蛋白,以可溶二聚體形式存在於血漿、以二聚體或多聚體形式存在于細胞表面並存在於細胞外基質。它參與細胞的黏附和遷移過程,包括胚胎發育、傷口癒合、血液凝固、宿主防禦和轉移 (RefSeq, 2002)。FN1 是一個重要的腫瘤相關血管生成靶向劑 (Sollini et al., 2015)。FN1 是胰腺癌的幾個生物標誌物之一 (Ansari et al., 2014)。FN1 是負責乳腺癌內分泌抗性的眾多因數之一。FN1 在乳腺癌中顯著失調,促進腫瘤進展和轉移擴散 (Oskarsson, 2013; Zheng et al., 2014)。它是鱗狀細胞癌中上皮-間質轉變的一種生物標誌物 (Scanlon et al., 2013)。FN1 在多發性骨髓瘤 中起重要作用 (Neri and Bahlis, 2012)。FN1 encodes
FUCA2,分泌人 α-L-岩藻糖苷酶 2,被確定為負責 L-岩藻糖轉移的關鍵酶。水解酶被發現對幽門螺桿菌黏附於人胃癌細胞至關重要,顯示出具有巨大潛力作為幽門螺旋桿菌相關胃癌症的診斷標誌物和治療靶標 (Liu et al., 2009)。FUCA2, secreting human α-L-fucosidase 2, was identified as the key enzyme responsible for L-fucose transfer. The hydrolase was found to be critical for H. pylori adhesion to human gastric cancer cells, showing great potential as a diagnostic marker and therapeutic target for H. pylori-associated gastric cancer (Liu et al., 2009).
GCG 編碼胰高血糖素。它是一種胰腺激素,透過刺激糖原分解和糖原異生抵消胰島素的葡萄糖降低作用。它是特定 G 蛋白偶聯受體的一種配體,其信號通路控制細胞增殖 (RefSeq, 2002)。GCG 受體成像似乎是評估胰腺 β 細胞質量的潛在工具。它也可能成為其他腫瘤(如胃泌素瘤、嗜鉻細胞瘤和甲狀腺髓樣癌)成像的靶標 (Hubalewska-Dydejczyk et al., 2015)。GCG 在結腸癌變中起著關鍵作用 (Kannen et al., 2013)。GCG 是神經內分泌腫瘤的一個新出現的示蹤劑 (Reubi and Maecke, 2008)。GCG codes for glucagon. It is a pancreatic hormone that counteracts the glucose-lowering effects of insulin by stimulating glycogenolysis and gluconeogenesis. It is a ligand for specific G protein-coupled receptors whose signaling pathways control cell proliferation (RefSeq, 2002). GCG receptor imaging appears to be a potential tool for assessing pancreatic β-cell mass. It may also be a target for imaging in other tumors such as gastrinoma, pheochromocytoma, and medullary thyroid carcinoma (Hubalewska-Dydejczyk et al., 2015). GCG plays a key role in colon carcinogenesis (Kannen et al., 2013). GCG is an emerging tracer for neuroendocrine tumors (Reubi and Maecke, 2008).
GFPT2 編碼穀氨醯胺果糖-6-磷酸轉氨酶 2,位於染色體 5q34-q35 上 (RefSeq, 2002)。GFPT2 在乳腺癌和淋巴細胞性白血病中起著重要作用 (Kuang et al., 2008; Simpson et al., 2012)。GFPT2 encodes glutamine fructose-6-phosphate transaminase 2 and is located on chromosomes 5q34-q35 (RefSeq, 2002). GFPT2 plays an important role in breast cancer and lymphocytic leukemia (Kuang et al., 2008; Simpson et al., 2012).
GPN1 編碼 GPN 環 GTP 酶 1,位於染色體 2p23.3 上 (RefSeq, 2002)。GPN1 是參與 DNA 修復基因 XPA(控制核苷酸切除修復信號通路的一個關鍵因數) 的核局部化的一種細胞質 GTP 酶。GPN1 encodes
GRIK2 編碼谷氨酸受體,離子型,鉀鹽鎂礬 2。此基因的突變與常染色體隱性精神發育遲滯相關 (RefSeq, 2002)。TRMT11-GRIK2 是在攝護腺癌中發現的幾個融合基因之一,與腫瘤侵襲性相關 (Yu et al., 2014)。GRIK2 SNP 與口腔癌風險或易感性增加有關 (Bhatnagar et al., 2012)。GRIK2 是肺癌的潛在生物標誌物 (Rauch et al., 2012)。染色體缺失導致的 GRIK2 失活可有助於促成 T 細胞淋巴瘤的發病。GRIK2 失活在胃癌變中發揮作用(Resende et al., 2011; Lopez-Nieva et al., 2012)。GRIK2 encodes a glutamate receptor, ionotropic, kale 2. Mutations in this gene are associated with autosomal recessive mental retardation (RefSeq, 2002). TRMT11-GRIK2 is one of several fusion genes found in prostate cancer and is associated with tumor aggressiveness (Yu et al., 2014). GRIK2 SNPs are associated with increased risk or susceptibility to oral cancer (Bhatnagar et al., 2012). GRIK2 is a potential biomarker for lung cancer (Rauch et al., 2012). Inactivation of GRIK2 by chromosomal deletion may contribute to the pathogenesis of T-cell lymphoma. GRIK2 inactivation plays a role in gastric carcinogenesis (Resende et al., 2011; Lopez-Nieva et al., 2012).
GRIK3 編碼谷氨酸受體,離子型,鉀鹽鎂礬 3。它屬於谷氨酸受體家族,是哺乳動物大腦中主要的興奮性神經遞質受體,在各種正常神經生理過程中被啟動 (RefSeq, 2002)。GRIK3 與肺腺癌(甲基化、功能修飾)、兒童中樞神經系統腫瘤、淋巴細胞性白血病和神經母細胞瘤相關 (Pradhan et al., 2013)。GRIK3 在中樞神經系統的幾個兒科腫瘤中差異表達 (Brocke et al., 2010)。GRIK3 encodes a glutamate receptor, an ionotropic,
GSK3B 編碼糖原合酶激酶 3β。它參與能量代謝、神經細胞發育和身體模式形成 (RefSeq, 2002)。GSK3B 的異常調節顯示出可促進一些癌症的細胞生長,而在另一些癌症中抑制細胞生長,並可能在食管癌中起重要作用 (Gao et al., 2014b)。GSK3B 在多形性膠質母細胞瘤中失調 (Atkins et al., 2013)。GSK3B 失調促進胃腸癌、胰腺癌和肝癌生長 (Miyashita et al., 2009)。GSK3B encodes glycogen synthase kinase 3β. It is involved in energy metabolism, nerve cell development and body patterning (RefSeq, 2002). Dysregulation of GSK3B has been shown to promote cell growth in some cancers and inhibit it in others, and may play an important role in esophageal cancer (Gao et al., 2014b). GSK3B is dysregulated in glioblastoma multiforme (Atkins et al., 2013). GSK3B dysregulation promotes the growth of gastrointestinal, pancreatic and liver cancers (Miyashita et al., 2009).
HLA-A 編碼 1A 類主要組織相容性複合體,透過表現內質網腔衍生的肽在免疫系統中發揮中心作用 (RefSeq, 2002)。HLA-A 抗原的損失是人類腫瘤的共同特徵。對於黑色素瘤、癌症、淋巴瘤、神經母細胞瘤和急性白血病,記錄了 HLA-A、HLA-B 和 HLA-C 陽性細胞百分比下降、特別抗原的選擇性喪失和 1 類分子表達的全部損失 (Garrido and Ruiz-Cabello, 1991; Salerno et al., 1990)。在胃癌和食管癌中,HLA-A 表達主要由 MAPK 通路調節,部分受 Akt 通路影響,在臨床腫瘤樣本中,p-Erk 表達和 HLA 1 類表達之間存在著很強的負相關性 (Mimura et al., 2013)。HLA-A encodes the class 1A major histocompatibility complex and plays a central role in the immune system by representing peptides derived from the lumen of the endoplasmic reticulum (RefSeq, 2002). Loss of HLA-A antigens is a common feature of human tumors. For melanoma, cancer, lymphoma, neuroblastoma, and acute leukemia, decreased percentages of HLA-A, HLA-B, and HLA-C positive cells, selective loss of specific antigens, and total loss of
HNRNPU(也稱為 SAF-A)編碼屬於異質核糖核蛋白RNA 結合亞家族 (hnRNP) 的異質核糖核蛋白 U,其與前體 mRNA 加工以及細胞核中的 mRNA 代謝和運輸相關。HNRNPU 被認為參與將 hnRNA 包裝成大型核糖核蛋白複合體 (RefSeq, 2002)。抑制肺癌轉移的 miR-193a-3p 上調會下調 HNRNPU 的表達 (Deng et al., 2015b)。長非編碼 RNA H19 可以透過與 HNRNPU/PCAF/RNAPol II 蛋白複合體的關聯性啟動 miR-200 的途徑,從而促進肝細胞癌中間充質至上皮細胞轉變以及腫瘤轉移的抑制 (Zhang et al., 2013d)。HNRNPU 與 SOX2 相互作用,SOX2 是維持胚胎和成體幹細胞幹性的關鍵基因,似乎在幾種人類癌症中被重新啟動 (Fang et al., 2011)。HNRNPU (also known as SAF-A) encodes a heterogeneous ribonucleoprotein U belonging to the RNA-binding subfamily of heterogeneous ribonucleoproteins (hnRNPs), which is involved in pre-mRNA processing and mRNA metabolism and trafficking in the nucleus. HNRNPU is thought to be involved in packaging hnRNAs into large ribonucleoprotein complexes (RefSeq, 2002). Upregulation of miR-193a-3p, which inhibits lung cancer metastasis, downregulates HNRNPU expression (Deng et al., 2015b). Long non-coding RNA H19 can initiate the miR-200 pathway through its association with the HNRNPU/PCAF/RNAPol II protein complex, thereby promoting the mesenchymal-to-epithelial transition of hepatocellular carcinoma and the suppression of tumor metastasis (Zhang et al., 2013d). HNRNPU interacts with SOX2, a gene critical for maintaining stemness in embryonic and adult stem cells that appears to be reactivated in several human cancers (Fang et al., 2011).
HSPA2 編碼睾丸特異性熱休克蛋白 70-2,對於精母細胞和癌細胞的生長是必不可少的。不同的研究表明,HSPA2 在宮頸癌、腎細胞癌和膀胱癌的疾病進展中起著重要作用。基因內多態性與胃癌的發生有關 (Ferrer-Ferrer et al., 2013; Garg et al., 2010a; Garg et al., 2010b; Singh and Suri, 2014)。HSPA2 encodes the testis-specific heat shock protein 70-2 and is essential for the growth of spermatocytes and cancer cells. Different studies have shown that HSPA2 plays an important role in the disease progression of cervical cancer, renal cell carcinoma and bladder cancer. Intragenic polymorphisms have been associated with gastric carcinogenesis (Ferrer-Ferrer et al., 2013; Garg et al., 2010a; Garg et al., 2010b; Singh and Suri, 2014).
HSPA8 被證明在食管鱗狀細胞癌中過量表達。HSPA8 在食管癌細胞中的高表達在體外抵消這些細胞的氧化應激誘導的細胞凋亡。此外,HSPA8 在多發性骨髓瘤和結腸癌中過量表達,HSPA8 的 BCR-ABL1-誘導表達促進慢性髓性白血病細胞的存活 (Chatterjee et al., 2013; Dadkhah et al., 2013; Jose-Eneriz et al., 2008; Kubota et al., 2010; Wang et al., 2013a)。HSPA8 was shown to be overexpressed in esophageal squamous cell carcinoma. High expression of HSPA8 in esophageal cancer cells counteracted oxidative stress-induced apoptosis in these cells in vitro. Furthermore, HSPA8 is overexpressed in multiple myeloma and colon cancer, and BCR-ABL1-inducible expression of HSPA8 promotes the survival of chronic myeloid leukemia cells (Chatterjee et al., 2013; Dadkhah et al., 2013; Jose-Eneriz et al. al., 2008; Kubota et al., 2010; Wang et al., 2013a).
HSPA8P8 是一種假基因 (RefSeq, 2002)。HSPA8P8 is a pseudogene (RefSeq, 2002).
HSPA9 編碼熱休克 70kDa 蛋白 9。該蛋白在細胞增殖、應激反應和線粒體維持中發揮作用 (RefSeq, 2002)。HSPA9 調節細胞過程,從病毒感染至神經變性,其中還包括癌變 (Flachbartova and Kovacech, 2013)。HSPA9 在肝細胞癌和結直腸癌中上調 (Rozenberg et al., 2013; Chen et al., 2014a; Kuramitsu and Nakamura, 2005)。HSPA9 在胃癌發展中發揮作用 (Ando et al., 2014)。HSPA9 是改善耐藥卵巢癌治療的潛在治療靶標 (Yang et al., 2013)。HSPA9 encodes the heat shock 70kDa protein 9. This protein plays a role in cell proliferation, stress response and mitochondrial maintenance (RefSeq, 2002). HSPA9 regulates cellular processes ranging from viral infection to neurodegeneration, including carcinogenesis (Flachbartova and Kovacech, 2013). HSPA9 is upregulated in hepatocellular carcinoma and colorectal cancer (Rozenberg et al., 2013; Chen et al., 2014a; Kuramitsu and Nakamura, 2005). HSPA9 plays a role in gastric cancer development (Ando et al., 2014). HSPA9 is a potential therapeutic target for improving the treatment of drug-resistant ovarian cancer (Yang et al., 2013).
IGDCC4 編碼免疫球蛋白超家族,DCC 子類,成員 4,位於染色體 15q22.31上 (RefSeq, 2002)。GDCC4 在肝細胞癌中表達 (Joy and Burns, 1988; Marquardt et al., 2011)。GDCC4 在急性淋巴細胞白血病中起作用 (Taylor et al., 2007)。IGDCC4 encodes the immunoglobulin superfamily, DCC subclass, member 4, located on chromosome 15q22.31 (RefSeq, 2002). GDCC4 is expressed in hepatocellular carcinoma (Joy and Burns, 1988; Marquardt et al., 2011). GDCC4 functions in acute lymphoblastic leukemia (Taylor et al., 2007).
IGF2BP3 編碼胰島素樣生長因數 II mRNA 結合蛋白 3,這是一種癌胚蛋白,其壓制胰島素樣生長因數 II 的翻譯 (RefSeq, 2002)。幾項研究表明,IGF2BP3 在細胞功能的各個重要方面發揮作用,例如細胞極化、遷移、形態、代謝、增殖和分化。體外研究表明,IGF2BP3 促進腫瘤細胞的增殖、黏附和侵襲。此外,IGF2BP3 已經顯示與侵襲性和晚期癌症相關 (Bell et al., 2013; Gong et al., 2014)。IGF2BP3 過度表達在許多腫瘤類型中已有描述,並與預後較差、腫瘤期別高和轉移相關,例如在神經母細胞瘤、結直腸癌、肝內膽管癌、肝細胞癌、攝護腺癌和腎細胞癌中過度表達 (Bell et al., 2013; Findeis-Hosey and Xu, 2012; Hu et al., 2014a; Szarvas et al., 2014; Jeng et al., 2009; Chen et al., 2011c; Chen et al., 2013; Hoffmann et al., 2008; Lin et al., 2013b; Yuan et al., 2009)。IGF2BP3 encodes insulin-like growth factor II mRNA-binding
IPO5 編碼輸入蛋白 5,是輸入蛋白 β 家族的一員。輸入蛋白是透過核孔複合體的蛋白易位必不可少的 (RefSeq, 2002)。IPO5 encodes
IPO7 編碼輸入蛋白 7。輸入蛋白 α/β 複合體和 GTP 酶 Ran 介導具有經典核定位元信號的蛋白質的核輸入 (RefSeq, 2002)。IPO7 經常在癌症中過度表達(Golomb et al., 2012)。IPO7 在膠質母細胞瘤、霍奇金淋巴瘤和乳腺癌中失調 (Jung et al., 2013; Ju et al., 2013; Nagel et al., 2014; Xue et al., 2015)。IPO7 是在攝護腺癌中下調的微 RNA 靶標 (Szczyrba et al., 2013)。結直腸癌中 IPO7 mRNA 表達水準升高與增殖增加有關 (Li et al., 2000)。IPO7 encodes importin 7. The importin alpha/beta complex and the GTPases Ran mediate the nuclear import of proteins with canonical nuclear localization metasignals (RefSeq, 2002). IPO7 is frequently overexpressed in cancer (Golomb et al., 2012). IPO7 is dysregulated in glioblastoma, Hodgkin lymphoma, and breast cancer (Jung et al., 2013; Ju et al., 2013; Nagel et al., 2014; Xue et al., 2015). IPO7 is a microRNA target downregulated in prostate cancer (Szczyrba et al., 2013). Elevated levels of IPO7 mRNA expression in colorectal cancer are associated with increased proliferation (Li et al., 2000).
IQGAP3 編碼含有 IQ 基序的 GAP 家族的一員,其在細胞信號傳導和細胞骨架之間的介面起作用。IQGAP3 調節 Rac1/Cdc42 促進的神經突向外生長,並直接與鈣調蛋白和肌球蛋白輕鏈相互作用 (Wang et al., 2007; Atcheson et al., 2011)。IQGAP3 在肺癌中過度表達,與腫瘤細胞生長、遷移和侵襲相關。此外,它在肝細胞癌中由染色體擴增上調,IQGAP3 表達在 p53 突變預後差的結直腸癌患者中增加 (Katkoori et al., 2012; Yang et al., 2014b; Skawran et al., 2008)。IQGAP3 調製所述 EGFR/Ras/ERK 信號級聯,並與 Rac/Cdc42 相互作用 (Yang et al., 2014b; Kunimoto et al., 2009)。IQGAP3 encodes a member of the GAP family containing the IQ motif, which functions at the interface between cell signaling and the cytoskeleton. IQGAP3 regulates Rac1/Cdc42-promoted neurite outgrowth and directly interacts with calmodulin and myosin light chains (Wang et al., 2007; Atcheson et al., 2011). IQGAP3 is overexpressed in lung cancer and is associated with tumor cell growth, migration and invasion. Furthermore, it is upregulated by chromosomal amplification in hepatocellular carcinoma, and IQGAP3 expression is increased in colorectal cancer patients with poor prognosis p53 mutation (Katkoori et al., 2012; Yang et al., 2014b; Skawran et al., 2008) . IQGAP3 modulates the EGFR/Ras/ERK signaling cascade and interacts with Rac/Cdc42 (Yang et al., 2014b; Kunimoto et al., 2009).
KDELR1 編碼 KDEL(賴氨酸 - 天冬氨酸 - 谷氨酸 - 亮氨酸)內質網蛋白質保留受體 1。KDELR1 在結構上和功能上類似於酵母 ERD2 基因產物 (RefSeq, 2002)。KDELR1 在腫瘤發生中發揮作用 (Yi et al., 2009)。在肝癌細胞中發現 KDELR1 水準降低 (Hou et al., 2015)。KDELR1 下調見於急性髓細胞白血病 (Caldarelli et al., 2013)。KDELR1 encodes the KDEL (lysine-aspartate-glutamate-leucine) endoplasmic reticulum
KPNA2 編碼核轉運蛋白 α2。KPNA2 可能參與蛋白質的核運輸 (RefSeq, 2002)。KPNA2 表達在上皮性卵巢癌中失調 (Lin et al., 2015)。KPNA2 在大口腔鱗狀細胞癌腫瘤中相比於在小腫瘤中下調 (Diniz et al., 2015)。 KPNA2 有助於關鍵蛋白的異常局部化,並導致乳腺癌的預後較差 (Alshareeda et al., 2015)。KPNA2 表達在上尿路上皮癌和子宮內膜癌中顯著上調 (Ikenberg et al., 2014; Shi et al., 2015)。KPNA2 促進肝細胞癌腫瘤生長 (Hu et al., 2014b)。KPNA2 encodes nuclear transport protein α2. KPNA2 may be involved in nuclear trafficking of proteins (RefSeq, 2002). KPNA2 expression is dysregulated in epithelial ovarian cancer (Lin et al., 2015). KPNA2 is downregulated in large oral squamous cell carcinoma tumors compared to small tumors (Diniz et al., 2015). KPNA2 contributes to the abnormal localization of key proteins and contributes to poor prognosis in breast cancer (Alshareeda et al., 2015). KPNA2 expression is significantly upregulated in upper urothelial and endometrial carcinomas (Ikenberg et al., 2014; Shi et al., 2015). KPNA2 promotes hepatocellular carcinoma tumor growth (Hu et al., 2014b).
KRT19 編碼角蛋白家族的一員。角蛋白是負責上皮細胞結構完整性的中間絲蛋白,細分為細胞角蛋白和毛髮角蛋白。KRT19 在周皮中特異性表達,周皮是包裹發育中表皮的暫時表層 (RefSeq, 2002)。腫瘤細胞中 KRT19 的表達是幾種腫瘤實體(如乳腺癌、肺癌、卵巢癌和肝細胞癌)的預後標誌物 (Skondra et al., 2014; Gao et al., 2014a; Liu et al., 2013a; Lee et al., 2013)。KRT19 已被證明是胰腺神經內分泌腫瘤(尤其是胰島素陰性腫瘤)的獨立預後因素。KRT19 陽性腫瘤與預後較差相關,不論既定病理參數怎樣,如大小、有絲分裂、淋巴管浸潤、壞死 (Jain et al., 2010)。KRT19 encodes a member of the keratin family. Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. KRT19 is specifically expressed in the periderm, the temporary surface layer that wraps the developing epidermis (RefSeq, 2002). KRT19 expression in tumor cells is a prognostic marker in several tumor entities such as breast, lung, ovarian and hepatocellular carcinoma (Skondra et al., 2014; Gao et al., 2014a; Liu et al., 2013a ; Lee et al., 2013). KRT19 has been shown to be an independent prognostic factor for pancreatic neuroendocrine tumors, especially insulin-negative tumors. KRT19-positive tumors are associated with poorer prognosis regardless of established pathological parameters, such as size, mitosis, lymphatic invasion, and necrosis (Jain et al., 2010).
KRT8(也稱為 CK8)編碼 II 型角蛋白家族的一員,與角蛋白 18 二聚化以形成單層上皮細胞的中間絲。KRT8 在維持細胞結構完整性中起作用,並且還具有信號轉導和細胞分化的功能 (RefSeq, 2002)。KRT8 上調,並從不同癌細胞(包括肺癌、攝護腺癌和乳腺癌)中分泌。高水準 KRT8 與遷移和侵襲增加 (Gonias et al., 2001; Kuchma et al., 2012; Fukunaga et al., 2002; Takei et al., 1995)。MEK/ERK 途徑在 Ser431 調節鞘氨醇磷脂膽鹼誘導的 KRT8 磷酸化。這導致角蛋白細胞骨架重組織,從而增強腫瘤細胞的遷移 (Busch et al., 2012)。腫瘤抑制因數 SMAR 下調 KRT8 的表達,這導致細胞遷移和侵襲性降低 (Pavithra et al., 2009; Mukhopadhyay and Roth, 1996)。KRT8 (also known as CK8) encodes a member of the type II keratin family and dimerizes with keratin 18 to form the intermediate filaments of epithelial monolayers. KRT8 plays a role in maintaining cellular structural integrity and also functions in signal transduction and cell differentiation (RefSeq, 2002). KRT8 is upregulated and secreted from different cancer cells including lung, prostate and breast cancer. High levels of KRT8 are associated with increased migration and invasion (Gonias et al., 2001; Kuchma et al., 2012; Fukunaga et al., 2002; Takei et al., 1995). MEK/ERK pathway regulates sphingosine phosphocholine-induced phosphorylation of KRT8 at Ser431. This leads to reorganization of the keratin cytoskeleton, which enhances tumor cell migration (Busch et al., 2012). The tumor suppressor SMAR downregulates KRT8 expression, which results in decreased cell migration and invasiveness (Pavithra et al., 2009; Mukhopadhyay and Roth, 1996).
KRT8P44 編碼角蛋白8 假基因 44,這位於染色體 6q26上 (RefSeq, 2002)。KRT8P44 encodes the keratin 8 pseudogene 44, which is located on chromosome 6q26 (RefSeq, 2002).
MACC1 編碼涉及細胞生長、上皮-間質轉變、血管生成、細胞運動性、侵襲性和轉移 的肝細胞生長因數 (HGF) 受體途徑的關鍵調節因數。MACC1 在許多癌症實體中,包括胃癌、結直腸癌、肺癌和乳腺癌中過度表達,並與癌症的進展、轉移和患者生存期差有關 (Huang et al., 2013b; Ma et al., 2013; Stein, 2013; Wang et al., 2015b; Wang et al., 2015m; Ilm et al., 2015)。MACC1 透過靶向作用于 β-連環蛋白和PI3K/AKT信號通路促進致癌作用,從而導致增加 c-Met 和 β-連環蛋白和其下游靶基因包括 c-Myc、細胞週期蛋白 D1、胱天蛋白酶 9、BAD 和 MMP9 (Zhen et al., 2014; Yao et al., 2015)。MACC1 encodes a key regulator of the hepatocyte growth factor (HGF) receptor pathway involved in cell growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness and metastasis. MACC1 is overexpressed in many cancer entities, including gastric, colorectal, lung, and breast cancer, and is associated with cancer progression, metastasis, and poor patient survival (Huang et al., 2013b; Ma et al., 2013; Stein, 2013; Wang et al., 2015b; Wang et al., 2015m; Ilm et al., 2015). MACC1 promotes carcinogenesis by targeting β-catenin and PI3K/AKT signaling pathways, resulting in increased c-Met and β-catenin and their downstream target genes including c-Myc, cyclin D1, caspase 9 , BAD and MMP9 (Zhen et al., 2014; Yao et al., 2015).
MAGED2編碼黑色素瘤抗原家族 D,2,是 Xp11.2(X 連鎖智力低下的熱點)中一個新定義的MAGE-D集群成員。MAGED2在特定腦區和在睾丸間質普遍呈高水準表達。MAGED2 是野生型 p53 活性的潛在負調節因數 (Langnaese et al., 2001; Papageorgio et al., 2007)。MAGED2 過度表達與黑素瘤、乳腺癌和結腸癌有關 (Li et al., 2004; Strekalova et al., 2015)。MAGED2, encoding melanoma antigen family D, 2, is a member of a newly defined MAGE-D cluster in Xp11.2, a hotspot of X-linked mental retardation. MAGED2 is generally expressed at high levels in specific brain regions and in the interstitium of the testis. MAGED2 is a potential negative regulator of wild-type p53 activity (Langnaese et al., 2001; Papageorgio et al., 2007). MAGED2 overexpression is associated with melanoma, breast and colon cancer (Li et al., 2004; Strekalova et al., 2015).
MAN2A1 編碼甘露 α 類 2A,成員 1,這位於高爾基體內,催化天冬醯胺連接的寡糖成熟途徑的最後水解步驟 (RefSeq, 2002)。苦馬豆素抑制 MAN2A1,造成 β 1,6-支鏈 N-連接聚糖產生抑制,這些聚糖與腫瘤細胞的惡性表型相關 (Yagel et al., 1990; Gerber-Lemaire and Juillerat-Jeanneret, 2010; Santos et al., 2011; Przybylo et al., 2005; Dennis and Laferte, 1987; Baptista et al., 1994; Goss et al., 1994; Fujieda et al., 1994; Korczak and Dennis, 1993; Roberts et al., 1998; Goss et al., 1997; Goss et al., 1995; Seftor et al., 1991)。MAN2A1 的 SNP 與兒童急性淋巴細胞白血病強烈有關 (Han et al., 2010)。MAN2A1 encodes manno-alpha class 2A,
MAP1A 編碼參與微管組裝(神經形成中的必要步驟)的微管相關蛋白 1A。MAP1A 積聚在視黃酸誘導的 P19 胚胎癌細胞中 (Vaillant and Brown, 1995)。MAP1A 在攝護腺癌的腫瘤相鄰基質中下調 (Zhu et al., 2015b)。MAP1A 可能在細胞增殖中發揮作用 (Matsuno et al., 2004)。Danusertib 顯著增加乳腺癌膜結合 MAP1A 的表達水準 (Li et al., 2015c)。黃芩素上調在肝癌細胞系 HepG2 中的 MAP1A (Wang et al., 2015l)。MAP1A 在皮膚鱗狀細胞癌中與 p62 呈負相關 (Yoshihara et al., 2014)。γ-生育三烯酚誘導 MAP1A 從其胞質增加轉化為其脂化同種型 (Tiwari et al., 2014)。MAP1A encodes the microtubule-associated protein 1A involved in microtubule assembly, an essential step in neurogenesis. MAP1A accumulates in retinoic acid-induced P19 embryonic carcinoma cells (Vaillant and Brown, 1995). MAP1A is downregulated in the tumor-adjacent stroma of prostate cancer (Zhu et al., 2015b). MAP1A may play a role in cell proliferation (Matsuno et al., 2004). Danusertib significantly increased the expression level of membrane-bound MAP1A in breast cancer (Li et al., 2015c). Baicalein up-regulated MAP1A in the liver cancer cell line HepG2 (Wang et al., 2015l). MAP1A inversely correlates with p62 in cutaneous squamous cell carcinoma (Yoshihara et al., 2014). γ-Tocotrienol induces the conversion of MAP1A from its cytoplasmic increase to its lipidated isoform (Tiwari et al., 2014).
MAT2A 編碼腺苷蛋氨酸 2A,催化從蛋氨酸和 ATP 產生 S-腺苷甲硫氨酸 (RefSeq, 2002)。MAT2A 在耐他莫昔芬 MCF-7 乳腺癌細胞中上調 (Phuong et al., 2015)。結腸癌中 SUMO 化和總 MAT2A 水準更高。UBC9、Bcl2 和 MAT2A 之間的相互作用增強了癌細胞的生長和存活 (Tomasi et al., 2015)。MAT2A 表達在腎細胞癌以及 S-腺苷甲硫氨酸治療的肝癌細胞系 WCH17 中下調 (Kuang et al., 2014; Wang et al., 2014b)。MAT1A:MAT2A 開關與肝細胞癌中的普遍 DNA 甲基化、降低的 DNA 修復、基因組不穩定性和信令失調相關 (Woodburn et al., 2013; Frau et al., 2013)。MAT2A在肝癌細胞癌、胃癌和結腸癌中上調 (Frau et al., 2012; Zhang et al., 2013e; Tomasi et al., 2013; Frau et al., 2013; Lo et al., 2013)。MAT2A 與胃癌患者的腫瘤分級、淋巴結轉移、腫瘤分化差相關 (Liu et al., 2011b; Zhang et al., 2013e)。MAT2A 是癌蛋白 MafK 的轉錄共抑制物 (Katoh et al., 2011)。MAT2A 與肝癌的腫瘤生長和進展有關聯 (Vazquez-Chantada et al., 2010; Liu et al., 2011a; Lu and Mato, 2008)。MAT2A encodes adenosylmethionine 2A and catalyzes the production of S-adenosylmethionine from methionine and ATP (RefSeq, 2002). MAT2A is upregulated in tamoxifen-resistant MCF-7 breast cancer cells (Phuong et al., 2015). Higher levels of SUMOylation and total MAT2A in colon cancer. The interaction between UBC9, Bcl2 and MAT2A enhances the growth and survival of cancer cells (Tomasi et al., 2015). MAT2A expression is downregulated in renal cell carcinoma as well as in S-adenosylmethionine-treated hepatoma cell line WCH17 (Kuang et al., 2014; Wang et al., 2014b). The MAT1A:MAT2A switch is associated with pervasive DNA methylation, decreased DNA repair, genomic instability, and dysregulated signaling in hepatocellular carcinoma (Woodburn et al., 2013; Frau et al., 2013). MAT2A is up-regulated in hepatoma, gastric and colon cancers (Frau et al., 2012; Zhang et al., 2013e; Tomasi et al., 2013; Frau et al., 2013; Lo et al., 2013). MAT2A is associated with tumor grade, lymph node metastasis, and poor tumor differentiation in gastric cancer patients (Liu et al., 2011b; Zhang et al., 2013e). MAT2A is a transcriptional co-repressor of the oncoprotein MafK (Katoh et al., 2011). MAT2A is associated with tumor growth and progression in liver cancer (Vazquez-Chantada et al., 2010; Liu et al., 2011a; Lu and Mato, 2008).
MBTPS2 是一種膜嵌入鋅金屬蛋白酶,其啟動參與轉錄固醇控制的蛋白信號傳導,在ER 應激反應中發揮作用 (Oeffner et al., 2009)。MBTPS2 is a membrane-embedded zinc metalloprotease that initiates signaling of proteins involved in sterol control of transcription and plays a role in the ER stress response (Oeffner et al., 2009).
MCM4 編碼微小染色體維持複合體組件 4,其為真核細胞基因組複製的啟動所必不可少的 (RefSeq, 2002)。MCM4 表達與上調的碳酸酐 IX 相關,碳酸酐 IX 是一種跨膜糖蛋白,其與幾種實體(包括食管癌)的生存和癌症進展有關 (Huber et al., 2015)。Has-miR-615-3p 可能透過調節 MCM4 牽涉鼻咽癌 (Chen et al., 2015b)。MCM4 可能在膀胱癌發展中發揮作用 (Zekri et al., 2015)。p53 獲取功能的突變增加 MCM4 在乳腺癌中的表達 (Polotskaia et al., 2015)。MCM4 在人類皮膚癌中有突變,顯示降低的 DNA 解旋酶的活性 (Ishimi and Irie, 2015)。MCM4 過度表達只與乳腺癌較短生存弱相關。MCM 複合體所有六個部分的過度表達與較短生存強烈相關 (Kwok et al., 2015)。 MCM4 在肺腺癌和喉鱗狀細胞癌中差異表達 (Lian et al., 2013; Zhang et al., 2014c)。MCM4 在宮頸癌中顯著過度表達 (Das et al., 2013; Das et al., 2015)。MCM4 可用作結直腸癌的一種生物標誌物 (Fijneman et al., 2012)。MCM4 encodes minichromosome maintenance complex component 4, which is essential for the initiation of genome replication in eukaryotic cells (RefSeq, 2002). MCM4 expression is associated with upregulated carbonic anhydride IX, a transmembrane glycoprotein that has been implicated in survival and cancer progression in several entities, including esophageal cancer (Huber et al., 2015). Has-miR-615-3p may be involved in nasopharyngeal carcinoma by regulating MCM4 (Chen et al., 2015b). MCM4 may play a role in bladder cancer development (Zekri et al., 2015). Gain-of-function mutations in p53 increase MCM4 expression in breast cancer (Polotskaia et al., 2015). MCM4 is mutated in human skin cancer and shows reduced DNA helicase activity (Ishimi and Irie, 2015). Overexpression of MCM4 was only weakly associated with shorter survival in breast cancer. Overexpression of all six parts of the MCM complex is strongly associated with shorter survival (Kwok et al., 2015). MCM4 is differentially expressed in lung adenocarcinoma and laryngeal squamous cell carcinoma (Lian et al., 2013; Zhang et al., 2014c). MCM4 is significantly overexpressed in cervical cancer (Das et al., 2013; Das et al., 2015). MCM4 can be used as a biomarker for colorectal cancer (Fijneman et al., 2012).
MIER1(也稱為 MI-ER1)編碼一種首先在非洲爪蟾中確定的轉錄調節因數 (RefSeq, 2002)。MIER1 在慢性骨髓性白血病 (CML) 和乳腺癌中上調,其中所述核轉錄變體 α 的損失與癌症進展和增殖相關 (McCarthy et al., 2008; Ding et al., 2003; Mascarenhas et al., 2014)。轉錄抑制因數 MIER1 由於與 HDAC1 的相互作用發揮功能 (Ding et al., 2003)。MIER1 (also known as MI-ER1) encodes a transcriptional regulator first identified in Xenopus (RefSeq, 2002). MIER1 is upregulated in chronic myeloid leukemia (CML) and breast cancer, where loss of the nuclear transcript variant α is associated with cancer progression and proliferation (McCarthy et al., 2008; Ding et al., 2003; Mascarenhas et al. , 2014). The transcriptional repressor MIER1 functions due to its interaction with HDAC1 (Ding et al., 2003).
MIR2861 是一種短的非編碼 RNA,其透過影響 mRNA 穩定性和翻譯參與基因表達的轉錄後調控 (RefSeq, 2002)。MIR2861 表達在伴淋巴結轉移的甲狀腺乳頭狀癌 (PTC) 中相比於無淋巴結轉移的 PTC 上調 (Wang et al., 2013f)。MIR2861 is a short noncoding RNA that is involved in the post-transcriptional regulation of gene expression by affecting mRNA stability and translation (RefSeq, 2002). MIR2861 expression is upregulated in papillary thyroid carcinoma (PTC) with lymph node metastasis compared to PTC without lymph node metastasis (Wang et al., 2013f).
MLEC 編碼 malectin 蛋白,這是 I 型膜錨定 ER 蛋白。MLEC 對 Glc2Man9GlcNAc2 (G2M9) N-聚糖具有親和力,並參與 ER 的調節糖基化。MLEC 也被證明可與核糖體結合糖蛋白 I 相互作用,並可能參與針對錯誤折疊蛋白的降解 (RefSeq, 2002; Pierce and Taniguchi, 2009)。MLEC 在結直腸癌中失調,在膠質母細胞瘤中增強 (Sethi et al., 2015; Demeure et al., 2016)。MLEC 可能是甲狀腺乳頭狀癌的一種生物標誌物 (Ban et al., 2012)。MLEC encodes the malectin protein, a type I membrane-anchored ER protein. MLECs have affinity for Glc2Man9GlcNAc2 (G2M9) N-glycans and are involved in regulated glycosylation of the ER. MLECs have also been shown to interact with ribosome-binding glycoprotein I and may be involved in the degradation of misfolded proteins (RefSeq, 2002; Pierce and Taniguchi, 2009). MLEC is dysregulated in colorectal cancer and enhanced in glioblastoma (Sethi et al., 2015; Demeure et al., 2016). MLEC may be a biomarker for papillary thyroid carcinoma (Ban et al., 2012).
MVP 編碼拱頂複合體的主要隔室,該蛋白質可透過調節 MAPK、JAK/STAT 和 PI3K/Akt 的信號途徑而在多種細胞過程中發揮作用。它還在多藥耐藥性、先天免疫、細胞存活和分化中發揮作用,該基因的表達可能是幾種類型癌症的預後標誌物 (RefSeq, 2002; Tucci et al., 2009; Lara et al., 2011; Scagliotti et al., 1999; van den Heuvel-Eibrink MM et al., 2000; Perez-Tomas, 2006; Scheffer et al., 2000; Ramachandran, 2007; Sekine et al., 2007; Lu and Shervington, 2008)。MVP 在幾種中樞神經系統腫瘤中高表達 (Yang et al., 2012a)。MVP 在癌症以及幾種化療耐藥癌細胞系中高表達 (Szaflarski et al., 2011; Mossink et al., 2003)。MVP 表達水準隨著年齡的增加而增加,並促進凋亡抗性 (Ryu and Park, 2009)。MVP encodes the major compartment of the vault complex, a protein that functions in a variety of cellular processes by regulating the signaling pathways of MAPK, JAK/STAT, and PI3K/Akt. It also plays a role in multidrug resistance, innate immunity, cell survival and differentiation, and the expression of this gene may be a prognostic marker in several types of cancer (RefSeq, 2002; Tucci et al., 2009; Lara et al. , 2011; Scagliotti et al., 1999; van den Heuvel-Eibrink MM et al., 2000; Perez-Tomas, 2006; Scheffer et al., 2000; Ramachandran, 2007; Sekine et al., 2007; Lu and Shervington, 2008). MVP is highly expressed in several CNS tumors (Yang et al., 2012a). MVP is highly expressed in cancer as well as in several chemotherapy-resistant cancer cell lines (Szaflarski et al., 2011; Mossink et al., 2003). MVP expression levels increase with age and promote apoptosis resistance (Ryu and Park, 2009).
MYBBP1A(也稱為 p160)編碼因其可與 Myb 原癌基因蛋白結合而被確定的一種核仁轉錄調節因數。MYBBP1A 可能在許多細胞過程,包括回應于核仁應力、腫瘤抑制和 核糖體 DNA 合成中發揮作用 (RefSeq, 2002)。MYBBP1A 在不同的癌症實體(包括肺癌、乳腺癌和頭頸癌)中失調。它與細胞增殖和轉移相關 (Bidkhori et al., 2013; George et al., 2015; Acuna Sanhueza et al., 2012; Akaogi et al., 2013)。MYBBP1A 透過 p53 活化以及 Myb 的結合促進轉錄活性,並透過影響染色體分離的控制導致 G2/M 阻滯或異常有絲分裂的細胞週期和有絲分裂 (Tavner et al., 1998; Tsuchiya et al., 2011; Mori et al., 2012; Ono et al., 2013)。MYBBP1A (also known as p160) encodes a nucleolar transcriptional regulator identified for its ability to bind to the Myb proto-oncogene protein. MYBBP1A may play a role in many cellular processes, including responses to nucleolar stress, tumor suppression, and ribosomal DNA synthesis (RefSeq, 2002). MYBBP1A is dysregulated in different cancer entities, including lung, breast, and head and neck cancers. It is associated with cell proliferation and metastasis (Bidkhori et al., 2013; George et al., 2015; Acuna Sanhueza et al., 2012; Akaogi et al., 2013). MYBBP1A promotes transcriptional activity through p53 activation as well as Myb binding and leads to G2/M arrest or aberrant mitotic cell cycle and mitosis through control of chromosome segregation (Tavner et al., 1998; Tsuchiya et al., 2011; Mori et al. al., 2012; Ono et al., 2013).
NCAPD2(也稱為 CNAP1)編碼非 SMC 縮合蛋白 I 複合體亞基 D2,其參與染色體縮合,並與阿爾茨海默氏病相關 (Ball, Jr. et al., 2002; Zhang et al., 2014b)。NCAPD2 過度表達發現於卵巢癌發展及腫瘤進展過程中的擴增和突變 (Emmanuel et al., 2011)。NCAPD2 (also known as CNAP1) encodes the non-SMC condensin I complex subunit D2, which is involved in chromosome condensation and is associated with Alzheimer's disease (Ball, Jr. et al., 2002; Zhang et al., 2014b ). NCAPD2 overexpression has been found to be amplified and mutated during ovarian cancer development and tumor progression (Emmanuel et al., 2011).
NCAPG 編碼非 SMC 縮合 I 複合體亞基 G,其負責有絲分裂和減數分裂期間染色體的縮合和穩定 (RefSeq, 2002)。NCAPG 在多發性骨髓瘤、急性骨髓性白血病患者中以及來自血液的白血病細胞或骨髓瘤細胞中下調 (Cohen et al., 2014)。NCAPG 可能是結直腸癌的多重抗藥性基因 (Li et al., 2012)。NCAPG 在嫌色亞型人類細胞癌中高度上調,但在常規人類腎細胞癌中不是這樣 (Kim et al., 2010a)。NCAPG 上調與黑色素瘤進展相關 (Ryu et al., 2007)。NCAPG 與葡萄膜黑色素瘤相關相關 (Van Ginkel et al., 1998)。NCAPG 在不同腫瘤細胞中表現出不同表達 (Jager et al., 2000)。NCAPG encodes the non-SMC condensation I complex subunit G, which is responsible for chromosome condensation and stabilization during mitosis and meiosis (RefSeq, 2002). NCAPG is downregulated in patients with multiple myeloma, acute myeloid leukemia, and in leukemia or myeloma cells from blood (Cohen et al., 2014). NCAPG may be a multidrug resistance gene in colorectal cancer (Li et al., 2012). NCAPG is highly upregulated in chromophobe subtype human cell carcinoma, but not in conventional human renal cell carcinoma (Kim et al., 2010a). Upregulation of NCAPG is associated with melanoma progression (Ryu et al., 2007). NCAPG has been associated with uveal melanoma (Van Ginkel et al., 1998). NCAPG is expressed differently in different tumor cells (Jager et al., 2000).
NLE1 編碼 WD40 重複蛋白家族的一個 notchless 同源物和成員,其透過不同信號通路參與胚胎發育,並似乎在核糖體的成熟中發揮作用 (Beck-Cormier et al., 2014; Romes et al., 2016; Lossie et al., 2012)。NLE1 encodes a notchless homologue and member of the WD40 repeat protein family that is involved in embryonic development through different signaling pathways and appears to play a role in ribosome maturation (Beck-Cormier et al., 2014; Romes et al., 2016 ; Lossie et al., 2012).
NOMO1(也稱為 PM5)編碼 Nodal 調節劑 1,這是可能屬於一種蛋白複合體的一種蛋白,該複合體參與脊椎動物發育過程中的 Nodal 信號傳導途徑 (RefSeq, 2002)。NOMO1 在攝護腺癌和 T 細胞淋巴瘤細胞中失調 (Stubbs et al., 1999; Lange et al., 2009)。NOMO1 (also known as PM5) encodes
NOMO2 編碼 Nodal 調節劑 2,這是可能屬於一種蛋白複合體的一種蛋白,該複合體參與脊椎動物發育過程中的 Nodal 信號傳導途徑 (RefSeq, 2002)。NOMO2 在上皮/間質細胞介面上調,以過渡到宮頸上皮內瘤變 (CIN) 3 和宮頸癌作為促侵襲基因組標記的一部分,這可能是上皮性腫瘤細胞過度擁擠的反應 (Gius et al., 2007)。NOMO2 encodes Nodal modulator 2, a protein that may belong to a protein complex involved in Nodal signaling during vertebrate development (RefSeq, 2002). NOMO2 is upregulated at the epithelial/mesenchymal interface for transition to cervical intraepithelial neoplasia (CIN) 3 and cervical cancer as part of a pro-invasive genomic signature, which may be a response to epithelial tumor cell overcrowding (Gius et al., 2007).
NOMO3 編碼 Nodal 調節劑 3,這是可能屬於一種蛋白複合體的一種蛋白,該複合體參與脊椎動物發育過程中的 Nodal 信號傳導途徑 (RefSeq, 2002)。NOMO3 被非小細胞肺癌的 DNA 甲基化失調 (Mullapudi et al., 2015)。NOMO3 是與卵巢癌組織糖基化相關的一種富集膜蛋白 (Allam et al., 2015)。NOMO3 encodes
NONO(也稱為 p54nrb)編碼含非 POU 結構域、與八聚體結合的蛋白。NONO 是一種 RNA 結合蛋白,在細胞核中發揮各種作用,包括轉錄調控和 RNA 剪接。此基因和轉錄因子 E3 之間的重新排列在乳頭狀腎細胞癌中觀察到 (RefSeq, 2002; Macher-Goeppinger et al., 2012)。NONO 表達與血管侵犯和存活降低強烈相關 (Barboro et al., 2008)。角骨海綿萜可能透過直接結合至 NONO 選擇性抑制適低氧癌細胞的生長 (Arai et al., 2016)。NONO 介導 MIA/CD-RAP 的行為,以促進惡性黑色素瘤的軟骨形成和進展 (Schmid et al., 2013)。NONO 表達與 c-Myc、細胞週期蛋白 D1 和 CDK4 的表達相關 (Nelson et al., 2012)。NONO 在 YB-1 過度表達的結直腸癌中的敲除可使它們對奧沙利鉑敏感 (Tsofack et al., 2011)。辛伐他汀強烈下調 NONO,並減少黑色素瘤進展 (Schiffner et al., 2011; Zanfardino et al., 2013)。NONO 在乳腺癌和黑色素瘤中過度表達 (Schiffner et al., 2011; Zhu et al., 2015d)。NONO (also known as p54nrb) encodes an octamer-binding protein containing a non-POU domain. NONO is an RNA-binding protein that performs various roles in the nucleus, including transcriptional regulation and RNA splicing. Rearrangements between this gene and transcription factor E3 have been observed in papillary renal cell carcinoma (RefSeq, 2002; Macher-Goeppinger et al., 2012). NONO expression is strongly associated with reduced vascular invasion and survival (Barboro et al., 2008). Ceraterpenes may selectively inhibit the growth of hypoxic cancer cells by directly binding to NONO (Arai et al., 2016). NONO mediates the behavior of MIA/CD-RAP to promote chondrogenesis and progression in malignant melanoma (Schmid et al., 2013). NONO expression correlates with expression of c-Myc, cyclin D1 and CDK4 (Nelson et al., 2012). Knockdown of NONO in YB-1-overexpressing colorectal cancers sensitized them to oxaliplatin (Tsofack et al., 2011). Simvastatin strongly downregulates NONO and reduces melanoma progression (Schiffner et al., 2011; Zanfardino et al., 2013). NONO is overexpressed in breast cancer and melanoma (Schiffner et al., 2011; Zhu et al., 2015d).
NPC1 編碼尼曼-皮克病,C1 型,這是一種大蛋白,其駐留在內涵體和溶酶體界膜中,並透過把膽固醇結合至它的 N-末端結構域介導細胞內膽固醇轉運 (RefSeq, 2002)。NPC1 的啟動子被低甲基化,NPC1 表達在食管癌中上調 (Singh et al., 2015)。NPC1 在同基因轉移癌細胞系、人胚胎幹細胞和人胚胎癌細胞中差異表達 (Lund et al., 2015; Dormeyer et al., 2008)。NPC1 降解由 Akt 調節。因此,NPC1 與宮頸癌的細胞增殖和遷移相關聯 (Du et al., 2015)。西地那非治療減少 NPC1 表達並殺死腦腫瘤幹細胞 (Booth et al., 2015)。膽固醇代謝的抑制劑,包括進行膽固醇吸收的 NPC1,被認為對治療癌症有益 (Ali-Rahmani et al., 2014)。NPC1 在 TNF-α 抗 MCF-7 乳腺癌細胞中上調 (Vincent et al., 2010; Moussay et al., 2011)。NPC1 encodes Niemann-Pick disease, type C1, a large protein that resides in the endosomal and lysosomal limiting membranes and mediates intracellular cholesterol transport by binding cholesterol to its N-terminal domain (RefSeq, 2002). The promoter of NPC1 is hypomethylated, and NPC1 expression is upregulated in esophageal cancer (Singh et al., 2015). NPC1 is differentially expressed in syngeneic metastatic cancer cell lines, human embryonic stem cells, and human embryonic carcinoma cells (Lund et al., 2015; Dormeyer et al., 2008). NPC1 degradation is regulated by Akt. Thus, NPC1 is associated with cell proliferation and migration in cervical cancer (Du et al., 2015). Sildenafil treatment reduces NPC1 expression and kills brain tumor stem cells (Booth et al., 2015). Inhibitors of cholesterol metabolism, including NPC1 for cholesterol absorption, are thought to be beneficial in the treatment of cancer (Ali-Rahmani et al., 2014). NPC1 is upregulated in TNF-α anti-MCF-7 breast cancer cells (Vincent et al., 2010; Moussay et al., 2011).
NPC2 編碼具有脂質識別結構域的蛋白質,可能透過晚期胞內體/溶酶體系統調節膽固醇的運輸。此基因的突變與尼曼-皮克病和額葉萎縮相關 (RefSeq, 2002)。NPC2 在不同癌症實體(包括乳腺癌、結腸癌、肺癌、腎癌和肝癌)中失調 (McDonald et al., 2004; Garcia-Lorenzo et al., 2012; Liao et al., 2013)。NPC 相關膽固醇擾動引導異常信號傳導途徑,導致 p38 MAPK 活化、Mdm2 介導的 p53 降解、ROCK 啟動和 RhoA 合成增加 (Qin et al., 2010)。NPC2 encodes a protein with a lipid recognition domain that may regulate cholesterol transport through the late endosome/lysosomal system. Mutations in this gene are associated with Niemann-Pick disease and frontal lobe atrophy (RefSeq, 2002). NPC2 is dysregulated in different cancer entities, including breast, colon, lung, kidney, and liver cancer (McDonald et al., 2004; Garcia-Lorenzo et al., 2012; Liao et al., 2013). NPC-associated cholesterol perturbation directs aberrant signaling pathways leading to p38 MAPK activation, Mdm2-mediated p53 degradation, ROCK initiation, and increased RhoA synthesis (Qin et al., 2010).
NUP160 編碼 160 kDa 的核孔蛋白,這是介導核質運輸的核孔複合體的一部分 (RefSeq, 2002)。NUP160-SLC43A3 是血管肉瘤中的一種復發融合癌基因,並與腫瘤進展相關 (Shimozono et al., 2015)。NUP160 encodes a 160 kDa nucleoporin that is part of the nuclear pore complex that mediates nucleocytoplasmic trafficking (RefSeq, 2002). NUP160-SLC43A3 is a recurrent fusion oncogene in angiosarcoma and is associated with tumor progression (Shimozono et al., 2015).
NUP205 編碼核孔蛋白 205kDa (RefSeq, 2002)。NUP205 被 TMEM209 穩定。這種相互作用是肺癌細胞增殖的關鍵驅動因數 (Fujitomo et al., 2012)。NUP205 encodes a nucleoporin of 205kDa (RefSeq, 2002). NUP205 is stabilized by TMEM209. This interaction is a key driver of lung cancer cell proliferation (Fujitomo et al., 2012).
NUP98 編碼核孔蛋白 98kDa,其參與許多細胞過程,包括核輸入、核輸出、有絲分裂進展和基因表達調控。這種基因與許多其他夥伴基因之間的基因易位已在不同的白血病中觀察到。重新排列通常形成該基因的 N-末端 GLGF 結構域與夥伴基因 C 末端的嵌合體 (RefSeq, 2002)。NUP98 重新排列誘導小鼠的白血病。它增強增殖並破壞原發性人類造血前體的分化 (Takeda and Yaseen, 2014)。導致 NUP98 重新排列的同源基因的失調導致白血病轉化 (Gough et al., 2011; De et al., 2014; Slape and Aplan, 2004; Grier et al., 2005; Abramovich et al., 2005; Nakamura, 2005; Shimada et al., 2000; Argiropoulos and Humphries, 2007)。NUP98 與造血系統惡性腫瘤(包括急性骨髓性白血病、原始細胞危象中慢性骨髓性白血病、骨髓增生異常徵候群、急性淋巴細胞性白血病和雙系列/雙表型白血病)中的幾個夥伴基因重新排列 (Tosic et al., 2009; Haznedaroglu and Beyazit, 2010; Shi et al., 2011; Gough et al., 2011; Panagopoulos et al., 2003; Morerio et al., 2006; Moore et al., 2007; Ahuja et al., 2001; McCormack et al., 2008; Lam and Aplan, 2001)。NUP98 與腫瘤發生相關聯 (Xu and Powers, 2009; Simon and Rout, 2014)。NUP98 是基因組穩定性的調節因數,並且是腫瘤發展的抑制因數 (Rao et al., 2009)。NUP98 encodes a nucleoporin of 98 kDa, which is involved in many cellular processes, including nuclear import, nuclear export, mitotic progression, and regulation of gene expression. Gene translocations between this gene and many other partner genes have been observed in different leukemias. Rearrangements often form a chimera of the gene's N-terminal GLGF domain with the C-terminus of a partner gene (RefSeq, 2002). NUP98 rearrangement induces leukemia in mice. It enhances proliferation and disrupts differentiation of primary human hematopoietic precursors (Takeda and Yaseen, 2014). Deregulation of homologous genes leading to rearrangement of NUP98 leads to leukemic transformation (Gough et al., 2011; De et al., 2014; Slape and Aplan, 2004; Grier et al., 2005; Abramovich et al., 2005; Nakamura, 2005; Shimada et al., 2000; Argiropoulos and Humphries, 2007). NUP98 is de novo reassorted with several partner genes in hematopoietic malignancies including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and biserial/biphenotypic leukemia permutations (Tosic et al., 2009; Haznedaroglu and Beyazit, 2010; Shi et al., 2011; Gough et al., 2011; Panagopoulos et al., 2003; Morerio et al., 2006; Moore et al., 2007; Ahuja et al., 2001; McCormack et al., 2008; Lam and Aplan, 2001). NUP98 is associated with tumorigenesis (Xu and Powers, 2009; Simon and Rout, 2014). NUP98 is a regulator of genome stability and a suppressor of tumor development (Rao et al., 2009).
OXSR1 編碼絲氨酸/蘇氨酸蛋白激酶,其調節回應于氧化應激的下游激酶並且可能在調節肌動蛋白細胞骨架中起到作用 (RefSeq, 2002)。OXSR1 在人類乳腺癌患者的腫瘤基質中上調,並且與復發有關 (Pavlides et al., 2010)。OXSR1 encodes a serine/threonine protein kinase that regulates downstream kinases in response to oxidative stress and may play a role in regulating the actin cytoskeleton (RefSeq, 2002). OXSR1 is upregulated in the tumor stroma of human breast cancer patients and is associated with recurrence (Pavlides et al., 2010).
PCSK9 編碼枯草桿菌蛋白酶類前蛋白轉化家族的一員,其包括透過分泌途徑的調控或組成分支處理蛋白質和肽前體轉運的蛋白酶。它在膽固醇和脂肪酸代謝中發揮作用 (RefSeq, 2002)。PCSK9 在不同癌症實體(包括肝癌、肺癌和胃癌)中失調 (Bhat et al., 2015; Marimuthu et al., 2013; Demidyuk et al., 2013)。PCSK9 缺乏透過其降低膽固醇水準的能力並透過增強 TNFα 介導的細胞凋亡而減少肝轉移。相反,其他研究顯示,膽固醇水準對癌症風險無影響 (Folsom et al., 2007; Sun et al., 2012)。PCSK9 encodes a member of the subtilisin-like preprotein transformation family, which includes proteases that handle the transport of protein and peptide precursors through regulation or constitutive branching of the secretory pathway. It plays a role in cholesterol and fatty acid metabolism (RefSeq, 2002). PCSK9 is dysregulated in different cancer entities including liver, lung and gastric cancer (Bhat et al., 2015; Marimuthu et al., 2013; Demidyuk et al., 2013). PCSK9 is deficient in reducing liver metastases through its ability to lower cholesterol levels and through enhancement of TNFα-mediated apoptosis. In contrast, other studies have shown that cholesterol levels have no effect on cancer risk (Folsom et al., 2007; Sun et al., 2012).
PDAP1 編碼磷蛋白,其可能上調成纖維細胞的 PDGFA 刺激生長,還下調 PDGFB 的促有絲分裂 (RefSeq, 2002)。PDAP1 在不同癌症類型(包括胃癌和直腸癌)中過度表達,並可能由此作為一種生物標誌物 (Choi et al., 2011; Marimuthu et al., 2013)。PDAP1 encodes a phosphoprotein that may upregulate PDGFA-stimulated growth in fibroblasts and also downregulate PDGFB mitogenicity (RefSeq, 2002). PDAP1 is overexpressed in different cancer types, including gastric and rectal cancer, and may thus serve as a biomarker (Choi et al., 2011; Marimuthu et al., 2013).
PDIA3(也稱為 ERp57)編碼蛋白二硫鍵異構酶家族成員 3,這是一種內質網蛋白質,與外源凝集素分子伴護、鈣網蛋白和鈣聯接蛋白相互作用以調節新合成糖蛋白的折疊 (RefSeq, 2002; Coe and Michalak, 2010)。PDIA3 可用作生物標志物和用於腫瘤診斷 (Shishkin et al., 2013)。PDIA3 在神經膠質瘤中分化表達 (Deighton et al., 2010)。PDIA3 牽涉人體病理,包括癌症和阿爾茨海默氏病 (Coe and Michalak, 2010)。PDIA3 是在 MHC I 類分子上載入病毒和自我肽的 TAP 輔助因數 (Coe and Michalak, 2010; Abele and Tampe, 2011)。PDIA3 (also known as ERp57) encodes protein disulfide
PFDN1 編碼前折疊蛋白亞基 1,是折疊蛋白的六個亞基之一,是一種分子伴護複合體,其結合並穩定新合成的多肽,從而使他們能夠正確地折疊 (RefSeq, 2002)。PFDN1 參與結腸直腸癌進展,並與腫瘤大小和浸潤呈正相關 (Wang et al., 2015e)。PFDN1 在包括結直腸癌的幾種癌症中上調 (Wang et al., 2015e)。PFDN1 作為鼻咽癌的參考基因 (Guo et al., 2010)。PFDN1 encodes
PHB 編碼擬在人類細胞衰老及抑制腫瘤中發揮作用的抑制素 (RefSeq, 2002; Mishra et al., 2010; Theiss and Sitaraman, 2011; Zhou and Qin, 2013; Mishra et al., 2005; McClung et al., 1995; Rajalingam and Rudel, 2005)。PHB 啟動參與細胞生長和惡性轉化的 Raf/MEK/ERK 通路 (Rajalingam and Rudel, 2005)。PHB 是鼻咽癌的一種潛在生物標誌物,可預測對放射療法的治療反應 (Chen et al., 2015e)。PHB 在耐藥癌細胞、藥物作用和疾病狀態組織的蛋白質組分析中被確定 (Guo et al., 2013)。PHB 在許多癌症實體中過度表達 (Zhou and Qin, 2013)。丙型肝炎病毒的核心蛋白是肝細胞癌的主要危險因素,其透過削弱抑制素誘導過度產生氧化應激 (Theiss and Sitaraman, 2011; Schrier and Falk, 2011; Koike, 2014)。PHB 在神經膠質瘤中分化表達 (Deighton et al., 2010)。PHB encodes a statin proposed to play a role in human cellular senescence and tumor suppression (RefSeq, 2002; Mishra et al., 2010; Theiss and Sitaraman, 2011; Zhou and Qin, 2013; Mishra et al., 2005; McClung et al. ., 1995; Rajalingam and Rudel, 2005). PHB initiates the Raf/MEK/ERK pathway involved in cell growth and malignant transformation (Rajalingam and Rudel, 2005). PHB is a potential biomarker in nasopharyngeal carcinoma that predicts treatment response to radiotherapy (Chen et al., 2015e). PHB was identified in proteomic analysis of drug-resistant cancer cells, drug action, and disease state tissues (Guo et al., 2013). PHB is overexpressed in many cancer entities (Zhou and Qin, 2013). The core protein of hepatitis C virus is a major risk factor for hepatocellular carcinoma, which induces excessive oxidative stress by attenuating inhibin (Theiss and Sitaraman, 2011; Schrier and Falk, 2011; Koike, 2014). PHB is differentially expressed in gliomas (Deighton et al., 2010).
PKM2 編碼參與糖酵解的丙酮酸激酶、肌肉、蛋白質。PKM2 與甲狀腺激素相互作用,因此可能介導甲狀腺激素誘導的細胞代謝作用。這也被認為參與細菌性發病 (RefSeq, 2002; Israelsen and Vander Heiden, 2015)。PKM2 被證明對癌細胞增殖和腫瘤生長很關鍵 (Chen et al., 2014b; Li et al., 2014c; DeLaBarre et al., 2014)。N-myc 基因作為髓母細胞瘤中 PKM2 的轉錄調節因數 (Tech et al., 2015)。PKM2 似乎在肝癌發病、上皮間質轉變和血管生成中發揮作用 (Nakao et al., 2014)。PKM2 是腫瘤學中 Warburg 效應的兩個關鍵因數之一 (Tamada et al., 2012; Warner et al., 2014; Ng et al., 2015)。PKM2 表達在癌細胞中上調 (Chaneton and Gottlieb, 2012; Luo and Semenza, 2012; Wu and Le, 2013)。在惡性細胞中,PKM2 具有糖酵解功能,作為轉錄輔啟動物和蛋白激酶。在後一種功能中,它易位至細胞核並磷酸化組蛋白 3,最終導致膠質母細胞瘤的細胞週期進展 (Semenza, 2011; Luo and Semenza, 2012; Tamada et al., 2012; Venneti and Thompson, 2013; Yang and Lu, 2013; Gupta et al., 2014; Iqbal et al., 2014; Chen et al., 2014b; Warner et al., 2014)。低活性二聚體 PKM2 不是活性四聚體形式可能在癌症中發揮作用 (Mazurek, 2011; Wong et al., 2015; Iqbal et al., 2014; Mazurek, 2007)。PKM2 encodes pyruvate kinase, muscle, protein involved in glycolysis. PKM2 interacts with thyroid hormones and thus may mediate thyroid hormone-induced cellular metabolism. This is also thought to be involved in bacterial pathogenesis (RefSeq, 2002; Israelsen and Vander Heiden, 2015). PKM2 has been shown to be critical for cancer cell proliferation and tumor growth (Chen et al., 2014b; Li et al., 2014c; DeLaBarre et al., 2014). The N-myc gene acts as a transcriptional regulator of PKM2 in medulloblastoma (Tech et al., 2015). PKM2 appears to play a role in liver cancer pathogenesis, epithelial-mesenchymal transition, and angiogenesis (Nakao et al., 2014). PKM2 is one of two key contributors to the Warburg effect in oncology (Tamada et al., 2012; Warner et al., 2014; Ng et al., 2015). PKM2 expression is upregulated in cancer cells (Chaneton and Gottlieb, 2012; Luo and Semenza, 2012; Wu and Le, 2013). In malignant cells, PKM2 functions in glycolysis, as a transcriptional co-promoter and as a protein kinase. In the latter function, it translocates to the nucleus and phosphorylates
PKP3 編碼橋粒斑菲素蛋白 3,是臂重複和橋粒斑菲素蛋白家族的一員,它位於橋粒和細胞核,並參與細胞骨架中鈣黏連接到中間絲。PKP3 可能在細胞橋粒依賴性黏附和信號傳導途徑中發揮作用 (RefSeq, 2002)。PKP3 mRNA 在胃腸道腫瘤患者的血液中增加可作為生物標誌物和疾病預後預測因素 (Valladares-Ayerbes et al., 2010)。PKP3 過度表達與乳腺癌、肺癌和攝護腺癌的預後不良相關,而膀胱癌的下調與侵襲性行為有關 (Furukawa et al., 2005; Breuninger et al., 2010; Demirag et al., 2012; Takahashi et al., 2012)。PKP3 喪失導致 MMP7 和 PRL3 蛋白質水準增加,這是細胞遷移和腫瘤形成所需要的 (Khapare et al., 2012; Basu et al., 2015b)。PKP3 encodes
PLEC 編碼血小板溶素家族成員網蛋白,這是一種參與細胞骨架和黏附複合體交聯和組織的蛋白 (Bouameur et al., 2014)。PLEC 在結直腸腺癌、頭頸部鱗狀細胞癌和胰腺癌中過度表達 (Lee et al., 2004; Katada et al., 2012; Bausch et al., 2011)。PLEC encodes a member of the thrombolysin family reticulin, a protein involved in the cross-linking and organization of the cytoskeleton and adhesion complexes (Bouameur et al., 2014). PLEC is overexpressed in colorectal adenocarcinoma, head and neck squamous cell carcinoma, and pancreatic cancer (Lee et al., 2004; Katada et al., 2012; Bausch et al., 2011).
PLXNA2 編碼叢蛋白 A2,其為信號蛋白共受體。PLXNA2 被認為可轉導來自信號蛋白 3A 和 3C 的信號 (RefSeq, 2002)。KIAA1199 結合至 PLXNA2,導致透過 EGFR 穩定和信號傳導抑制信號蛋白 3A 介導的細胞死亡 (Shostak et al., 2014)。PLXNA2 在 TMPRSS2-ERG 陽性攝護腺癌和轉移性攝護腺癌中上調,從而增強細胞的遷移和侵襲 (Tian et al., 2014)。PLXNA2 在侵襲性更高的乳腺癌中表達水準更高,並與腫瘤發生有關 (Gabrovska et al., 2011)。PLXNA2 encodes plexin A2, a signaling protein coreceptor. PLXNA2 is thought to transduce signals from signaling proteins 3A and 3C (RefSeq, 2002). KIAA1199 binds to PLXNA2, resulting in inhibition of semaphorin 3A-mediated cell death via EGFR stabilization and signaling inhibition (Shostak et al., 2014). PLXNA2 is upregulated in TMPRSS2-ERG-positive and metastatic prostate cancer, thereby enhancing cell migration and invasion (Tian et al., 2014). PLXNA2 is expressed at higher levels in more aggressive breast cancers and has been implicated in tumorigenesis (Gabrovska et al., 2011).
POLA2 編碼 DNA 聚合酶 α 的輔助亞基(也稱為 0/68 kDa 或 B 亞基),透過束縛催化亞基 A 和引發酶複合體在 DNA 複製啟動中起重要作用 (Collins et al., 1993; Pollok et al., 2003)。POLA2 在不同癌症類型(包括胃腸道間質瘤和非小細胞肺癌)中失調 (Mah et al., 2014; Kang et al., 2015)。在 S 期,POLA2 附著到端粒。它與端粒酶活性相關,對於透過填充合成進行正確的端粒懸垂處理很重要 (Diotti et al., 2015)。POLA2 encodes the helper subunit (also known as the 0/68 kDa or B subunit) of DNA polymerase alpha and plays an important role in the initiation of DNA replication by tethering the catalytic subunit A and the primase complex (Collins et al., 1993 ; Pollok et al., 2003). POLA2 is dysregulated in different cancer types, including gastrointestinal stromal tumors and non-small cell lung cancer (Mah et al., 2014; Kang et al., 2015). During S phase, POLA2 attaches to telomeres. It correlates with telomerase activity and is important for proper telomere overhang processing by stuffer synthesis (Diotti et al., 2015).
PPM1G 編碼蛋白磷酸酶,Mg2+/Mn2+ 依賴性,1G。這種蛋白被發現負責前 mRNA 剪接因數的磷酸化,這對功能性剪接體形成非常重要 (RefSeq, 2002)。 PPM1G 調節 E3 連接酶 WWP2,其差異性調節細胞 p73 和 δNp73 (Chaudhary and Maddika, 2014)。 PPM1G 能夠結合 p53 的凋亡刺激蛋白,它們在各種實體中獨特地過度表達 (Skene-Arnold et al., 2013)。PPM1G 透過去磷酸化下調 USP7S,導致 p53 蛋白累積 (Khoronenkova et al., 2012)。PPM1G encodes a protein phosphatase, Mg2+/Mn2+ dependent, 1G. This protein was found to be responsible for the phosphorylation of pre-mRNA splicing factors, which are important for functional spliceosome formation (RefSeq, 2002). PPM1G regulates the E3 ligase WWP2, which differentially regulates cellular p73 and δNp73 (Chaudhary and Maddika, 2014). PPM1G is capable of binding apoptosis-stimulating proteins of p53, which are uniquely overexpressed in various entities (Skene-Arnold et al., 2013). PPM1G downregulates USP7S through dephosphorylation, resulting in accumulation of p53 protein (Khoronenkova et al., 2012).
PPP1R15B 編碼蛋白磷酸酶 1 (PP1) 相互作用蛋白。PPP1R15B 透過 PP1 催化亞基的招募促進轉錄起始因數 EIF2-α 的去磷酸化 (RefSeq, 2002)。由於細胞週期從 G1 到 S 期的不成功過渡、透過增加胱天蛋白酶 3/7 活性誘導凋亡和ER α 活性的調節,PPP1R15B 的下調導致增殖受損 (Shahmoradgoli et al., 2013)。PPP1R15B encodes a protein phosphatase 1 (PP1) interacting protein. PPP1R15B promotes dephosphorylation of the transcription initiation factor EIF2-α through recruitment of the catalytic subunit of PP1 (RefSeq, 2002). Downregulation of PPP1R15B results in impaired proliferation due to unsuccessful transition of the cell cycle from G1 to S phase, induction of apoptosis through increased
PPY 編碼一種蛋白,在郎格罕氏胰島中合成為一個 95 氨基酸多肽前體。它被裂解成兩個肽產物;36 個氨基酸的活性激素和未知功能的一個二十肽。該激素作為胰腺和胃腸功能的調節因數,可能在食物攝入量的調節中非常重要 (RefSeq, 2002)。繼發於胰腺癌的糖尿病患者與 2 型糖尿病患者相比,對混合膳食具有遲鈍的 PPY 回應。然而,遲鈍的 PPY 響應僅在那些腫瘤位於胰頭部位的胰腺癌患者中觀察到 (Hart et al., 2015)。PPY encodes a protein that is synthesized in islets of Langerhans as a 95 amino acid polypeptide precursor. It is cleaved into two peptide products; an active hormone of 36 amino acids and an eicoseptide of unknown function. This hormone acts as a regulator of pancreatic and gastrointestinal function and may be important in the regulation of food intake (RefSeq, 2002). Patients with diabetes secondary to pancreatic cancer have a blunted PPY response to mixed diets compared with patients with type 2 diabetes. However, blunted PPY responses were only observed in those patients with pancreatic cancer whose tumors were located in the pancreatic head (Hart et al., 2015).
PRKDC 編碼 DNA 依賴性蛋白激酶 (DNA-PK) 的催化亞基 (RefSeq, 2002)。PRKDC 是子宮內膜異位症相關卵巢癌和乳腺癌中常見的突變基因 (Er et al., 2016; Wheler et al., 2015)。在結直腸癌中,與正常組織相比,PRKDC 在癌組織中上調。PRKDC 高表達的患者表現出較差的總生存期 (Sun et al., 2016b)。PRKDC encodes the catalytic subunit of DNA-dependent protein kinase (DNA-PK) (RefSeq, 2002). PRKDC is a frequently mutated gene in endometriosis-related ovarian and breast cancers (Er et al., 2016; Wheler et al., 2015). In colorectal cancer, PRKDC is upregulated in cancerous tissues compared to normal tissues. Patients with high PRKDC expression showed poor overall survival (Sun et al., 2016b).
PSEN1 編碼早老素 1,這與阿爾茨海默氏病相關聯。它是 Notch 啟動所需 γ-分泌複合體的一部分 (RefSeq, 2002; Ponnurangam et al., 2015)。小干擾 RNA 過度表達 PSEN1 使得化療耐藥膀胱癌細胞對藥物觸發細胞死亡敏感 (Deng et al., 2015a)。PSEN1 透過下調 E-鈣黏蛋白在上皮-間質轉化和化學耐藥中起關鍵作用 (Sehrawat et al., 2014; Dinicola et al., 2016)。TRAF6 介導的 PSEN1 啟動導致促進腫瘤的侵襲性 (Gudey et al., 2014; Sundar et al., 2015)。γ-分泌複合體的下調表達被認為是乳腺癌特異性死亡的危險因素 (Peltonen et al., 2013)。PSEN1 在 Notch1 失調引起的 T 細胞急性淋巴細胞白血病中差異表達 (Paryan et al., 2013)。PSEN1 在口腔鱗癌細胞系和分離自口腔鱗狀細胞癌組織的原發性口腔角質形成細胞中過度表達。 PSEN1 過度表達透過影響 P-鈣黏蛋白導致口腔鱗狀細胞癌的細胞黏附減少 (Bauer et al., 2013)。內源性大麻素花生四烯酸增加 PSEN1 在膽管癌中的表達和招募 (Frampton et al., 2010)。p53 能夠調節 PSEN1 的表達 (Checler et al., 2010)。PSEN1 參與腫瘤逆轉 (Telerman and Amson, 2009)。PSEN1 encodes
PSEN2 編碼早老素 2,這與阿爾茨海默氏病相關聯。它是 Notch 啟動所需 γ-分泌複合體的一部分 (RefSeq, 2002)。氧化應激和 p53 表達水準在攜帶突變 PSEN2 基因的 PC12 細胞中增加 (Nguyen et al., 2007)。PSEN2 是乳腺癌的一種有用的預後因數。新型 PSEN2 等位基因 R62H 和 R71W 影響 PSEN2 的功能,並且可能對乳腺癌易患性產生中度風險 (To et al., 2006; Xu et al., 2006)。PSEN2 是 10 個基因標記集的一部分,其與卵巢癌無復發生存期有關,但與總體生存時間無關 (Chen and Liu, 2015)。PSEN2 缺失可能透過 iPLA2 導致肺腫瘤發生 (Yun et al., 2014)。γ-分泌複合體的下調表達被認為是乳腺癌特異性死亡的危險因素 (Peltonen et al., 2013)。PSEN2 在巨核細胞白血病和胃癌中差異表達。PSEN2 表達與腫瘤類型、UICC 腫瘤分期、腫瘤分級和患者生存相關 (Warneke et al., 2013; Hao et al., 2006)。PSEN2 啟動子在神經膠質瘤組織被去甲基化,引起 PSEN2 過度表達 (Liu et al., 2012)。在膽管癌中,2-花生醯基甘油增加 PSEN2 的表達和募集 (Frampton et al., 2010)。在大鼠胰腺癌中,PSEN2透過裂解 EpC 引起腫瘤細胞增殖 (Maetzel et al., 2009; Thuma and Zoller, 2013)。PSEN2 encodes presenilin 2, which is associated with Alzheimer's disease. It is part of the γ-secretory complex required for Notch initiation (RefSeq, 2002). Oxidative stress and p53 expression levels were increased in PC12 cells harboring a mutant PSEN2 gene (Nguyen et al., 2007). PSEN2 is a useful prognostic factor for breast cancer. Novel PSEN2 alleles R62H and R71W affect PSEN2 function and may confer moderate risk for breast cancer susceptibility (To et al., 2006; Xu et al., 2006). PSEN2 is part of a set of 10 gene signatures that are associated with ovarian cancer recurrence-free survival, but not overall survival time (Chen and Liu, 2015). Loss of PSEN2 may contribute to lung tumorigenesis through iPLA2 (Yun et al., 2014). Downregulated expression of the γ-secretory complex is considered a risk factor for breast cancer-specific mortality (Peltonen et al., 2013). PSEN2 is differentially expressed in megakaryocytic leukemia and gastric cancer. PSEN2 expression correlates with tumor type, UICC tumor stage, tumor grade, and patient survival (Warneke et al., 2013; Hao et al., 2006). The PSEN2 promoter is demethylated in glioma tissue, resulting in PSEN2 overexpression (Liu et al., 2012). In cholangiocarcinoma, 2-arachidonylglycerol increases PSEN2 expression and recruitment (Frampton et al., 2010). In rat pancreatic cancer, PSEN2 causes tumor cell proliferation by cleaving EpC (Maetzel et al., 2009; Thuma and Zoller, 2013).
PTGS1(也稱為 COX1)編碼攝護腺素內過氧化物合酶 1(攝護腺素 G/H 合酶和環加氧酶)。PTGS1 組成型表達並催化花生四烯酸酯轉化為攝護腺素。所編碼的蛋白質調節內皮細胞的血管生成,並且被非甾體抗炎藥物(如阿司匹林)抑制。根據其既可作為環氧合酶也可作為過氧化物酶的能力,PTGS1 已被確定為一個兼職功能蛋白質。該蛋白質可在腫瘤進展過程中促進細胞增殖 (RefSeq, 2002; Tietz et al., 2013)。PTGS1 可能參與腫瘤發生 (Rouzer and Marnett, 2009)。增強腫瘤生長透過在攝護腺素和 VEGF 產生中發揮作用的 PTGS1 上調得到支援 (Campione et al., 2015)。PTGS1 與復發性小唾液腺癌生存率降低相關 (Haymerle et al., 2015)。PTGS1 與乳腺癌的發生有關 (Basu et al., 2015a; Serra et al., 2016)。PTGS1 經常在癌症進展中失調節 (Karnezis et al., 2012)。PTGS1 的缺失導致基底細胞癌的大量減少 (Arbiser, 2010)。阿司匹林抑制 PTGS1 誘導的血小板活化,這被認為參與炎症和癌症的發展,包括結直腸癌、頭頸癌、胃腸癌和胰腺癌 (Pereira et al., 2009; Perrone et al., 2010; Schror, 2011; Garcia Rodriguez et al., 2013; Bruno et al., 2012; Yue et al., 2014; Sostres et al., 2014; Schror and Rauch, 2013; Guillem-Llobat et al., 2014; Patrignani and Patrono, 2015; Patrono, 2015; Dovizio et al., 2015; Jimenez et al., 2007; Klass and Shin, 2007)。PTGS1 (also known as COX1) encodes prostaglandin endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase). PTGS1 is constitutively expressed and catalyzes the conversion of arachidonic acid to prostaglandins. The encoded protein regulates endothelial cell angiogenesis and is inhibited by non-steroidal anti-inflammatory drugs such as aspirin. Based on its ability to function as both a cyclooxygenase and a peroxidase, PTGS1 has been identified as a part-time functional protein. This protein promotes cell proliferation during tumor progression (RefSeq, 2002; Tietz et al., 2013). PTGS1 may be involved in tumorigenesis (Rouzer and Marnett, 2009). Enhanced tumor growth is supported by upregulation of PTGS1, which plays a role in prostaglandin and VEGF production (Campione et al., 2015). PTGS1 is associated with reduced survival in recurrent minor salivary gland carcinoma (Haymerle et al., 2015). PTGS1 has been implicated in the development of breast cancer (Basu et al., 2015a; Serra et al., 2016). PTGS1 is frequently deregulated in cancer progression (Karnezis et al., 2012). Deletion of PTGS1 results in a substantial reduction in basal cell carcinoma (Arbiser, 2010). Aspirin inhibits PTGS1-induced platelet activation, which is thought to be involved in inflammation and the development of cancers, including colorectal, head and neck, gastrointestinal, and pancreatic cancers (Pereira et al., 2009; Perrone et al., 2010; Schror, 2011; Garcia Rodriguez et al., 2013; Bruno et al., 2012; Yue et al., 2014; Sostres et al., 2014; Schror and Rauch, 2013; Guillem-Llobat et al., 2014; Patrignani and Patrono, 2015; Patrono, 2015; Dovizio et al., 2015; Jimenez et al., 2007; Klass and Shin, 2007).
PTGS2(也稱為 COX-2)編碼攝護腺素內過氧化物合酶 2(環氧合酶),這是攝護腺素生物合成中充當雙加氧酶和過氧化物酶的關鍵酶 (RefSeq, 2002)。PTGS2 和攝護腺素的表達與多種癌症類型相關,包括乳腺癌、肺癌、胃癌、胰腺癌、結直腸癌和攝護腺癌。表達水準也與腫瘤侵襲性(包括轉移)成正比 (Shao et al., 2012; Kunzmann et al., 2013; Misra and Sharma, 2014; Aziz and Qiu, 2014; Thill et al., 2014; Knab et al., 2014; Huang and Huang, 2014; Wang et al., 2014c)。具有抗 PTGS2 活性的抗炎劑對癌症的化學預防具有巨大潛力 (Harris, 2009; Ghosh et al., 2010)。PTGS2 (also known as COX-2) encodes prostaglandin endoperoxide synthase 2 (cyclooxygenase), a key enzyme in prostaglandin biosynthesis that acts as a dioxygenase and peroxidase (RefSeq, 2002). The expression of PTGS2 and prostaglandins is associated with multiple cancer types, including breast, lung, gastric, pancreatic, colorectal, and prostate cancers. Expression levels are also proportional to tumor aggressiveness, including metastasis (Shao et al., 2012; Kunzmann et al., 2013; Misra and Sharma, 2014; Aziz and Qiu, 2014; Thill et al., 2014; Knab et al. ., 2014; Huang and Huang, 2014; Wang et al., 2014c). Anti-inflammatory agents with anti-PTGS2 activity have great potential for cancer chemoprevention (Harris, 2009; Ghosh et al., 2010).
PTPN14 編碼蛋白酪氨酸磷酸酶,非受體型 14,其顯示可調節哺乳動物的淋巴發育。在淋巴水腫-後鼻孔閉鎖的親屬中發現失功能突變 (RefSeq, 2002)。PTPN14 誘導 TGF-β 信號傳導,調節內皮間質轉變和器官形成 (Wyatt and Khew-Goodall, 2008)。PTPN14 在膽管癌中下調,並與臨床病理特徵和生存呈負相關 (Wang et al., 2015d; Wang et al., 2015c)。PTPN14 抑制可溶性和膜結合蛋白的轉運,從而阻止轉移 (Belle et al., 2015)。PTPN14 負調節癌蛋白 Yes 相關蛋白 (YAP),這是河馬途徑中的關鍵蛋白質,其負責器官大小和腫瘤發生 (Liu et al., 2013b; Huang et al., 2013a; Lin et al., 2013a)。PTPN14 的失功能突變牽涉神經母細胞瘤復發、乳腺癌和結直腸癌 (Laczmanska and Sasiadek, 2011; Wang et al., 2004; Schramm et al., 2015; Wyatt and Khew-Goodall, 2008)。PTPN14 encodes a protein tyrosine phosphatase, non-receptor type 14, which has been shown to regulate lymphoid development in mammals. Loss-of-function mutations were found in relatives of lymphedema-posterior nostril atresia (RefSeq, 2002). PTPN14 induces TGF-β signaling and regulates endothelial-mesenchymal transition and organogenesis (Wyatt and Khew-Goodall, 2008). PTPN14 is downregulated in cholangiocarcinoma and negatively correlated with clinicopathological features and survival (Wang et al., 2015d; Wang et al., 2015c). PTPN14 inhibits the transport of soluble and membrane-bound proteins, thereby preventing metastasis (Belle et al., 2015). PTPN14 negatively regulates the oncoprotein Yes-associated protein (YAP), a key protein in the hippo pathway responsible for organ size and tumorigenesis (Liu et al., 2013b; Huang et al., 2013a; Lin et al., 2013a) . Loss of function mutations in PTPN14 have been implicated in neuroblastoma recurrence, breast and colorectal cancers (Laczmanska and Sasiadek, 2011; Wang et al., 2004; Schramm et al., 2015; Wyatt and Khew-Goodall, 2008).
RABGGTB 是 Rab 異戊二烯基轉移酶的 β 亞基,其催化 Rab GTP 酶的翻譯後四異戊二烯化 (Pylypenko et al., 2003)。RABGGTB 在化療難治性彌漫性大 B 細胞淋巴瘤中過度表達 (Linderoth et al., 2008)。RABGGTB is the beta subunit of Rab prenyltransferase, which catalyzes the post-translational tetraprenylation of Rab GTPases (Pylypenko et al., 2003). RABGGTB is overexpressed in chemotherapy-refractory diffuse large B-cell lymphoma (Linderoth et al., 2008).
RAC1 編碼 ras 相關 C3 肉毒桿菌毒素底物 1(rho 家族,小 GTP 結合蛋白 Rac1),是一種屬於小 GTP 結合蛋白的 RAS 超家族的 GTP 酶。該超家族的成員似乎調節多樣化的細胞活動,包括細胞生長的控制、細胞骨架重組以及蛋白激酶的啟動 (RefSeq, 2002)。RAC1 對於神經脊發育很重要,可防止黑色素瘤的形成 (Shakhova, 2014)。RAC1 可被肝細胞生長因數和蛋氨酸酪氨酸激酶受體啟動,從而導致內皮細胞的增殖和遷移 (Barrow-McGee and Kermorgant, 2014; Gallo et al., 2015)。RAC1 在卡波西肉瘤病毒癌變中誘導 ROS (Mesri et al., 2013)。RAC1 參與黑色素瘤發生和發展,並牽涉乳腺癌和頭頸部腫瘤 (Alan and Lundquist, 2013; Imianitov, 2013; Meierjohann, 2014)。Tiam1 能夠調節 RAC1,這反過來又參與細胞骨架活性、細胞極性、內吞作用和膜運輸、細胞遷移、黏附和侵襲、細胞生長和存活、轉移、血管生成和致癌作用的信號途徑 (Bid et al., 2013; Boissier and Huynh-Do, 2014)。RAC1 被認為是一種致癌基因 (Kunz, 2013; Kunz, 2014)。RAC1 突變可以引起多種疾病,包括惡性轉化 (Read, 2013; Chi et al., 2013)。Rac1 啟動導致肌動蛋白應力纖維、膜皺褶、板狀偽足和絲狀偽足的形成 (Klopocka et al., 2013; van and van Buul, 2012; Lane et al., 2014)。RAC1 在星形細胞瘤中下調,但在髓母細胞瘤中過度表達 (Khalil and El-Sibai, 2012)。RAC1 encodes ras-related C3 botulinum toxin substrate 1 (rho family, small GTP-binding protein Rac1), a GTPase belonging to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate diverse cellular activities, including control of cell growth, cytoskeletal reorganization, and initiation of protein kinases (RefSeq, 2002). RAC1 is important for neural crest development and prevents melanoma formation (Shakhova, 2014). RAC1 is activated by hepatocyte growth factor and methionine tyrosine kinase receptors, leading to endothelial cell proliferation and migration (Barrow-McGee and Kermorgant, 2014; Gallo et al., 2015). RAC1 induces ROS in Kaposi's sarcoma virus carcinogenesis (Mesri et al., 2013). RAC1 is involved in melanoma initiation and progression and has been implicated in breast and head and neck tumors (Alan and Lundquist, 2013; Imianitov, 2013; Meierjohann, 2014). Tiam1 is able to regulate RAC1, which in turn is involved in signaling pathways involved in cytoskeletal activity, cell polarity, endocytosis and membrane trafficking, cell migration, adhesion and invasion, cell growth and survival, metastasis, angiogenesis, and carcinogenesis (Bid et al. ., 2013; Boissier and Huynh-Do, 2014). RAC1 is considered an oncogene (Kunz, 2013; Kunz, 2014). RAC1 mutations can cause a variety of diseases, including malignant transformation (Read, 2013; Chi et al., 2013). Rac1 priming leads to the formation of actin stress fibers, membrane ruffles, lamellipodia, and filopodia (Klopocka et al., 2013; van and van Buul, 2012; Lane et al., 2014). RAC1 is downregulated in astrocytomas but overexpressed in medulloblastomas (Khalil and El-Sibai, 2012).
RAC3 編碼 ras 相關 C3 肉毒桿菌毒素底物 3(rho 家族,小 GTP 結合蛋白 Rac3),是一種屬於小 GTP 結合蛋白的 RAS 超家族的 GTP 酶。該超家族的成員似乎調節多樣化的細胞活動,包括細胞生長的控制、細胞骨架重組以及蛋白激酶的啟動 (RefSeq, 2002)。RAC3 的過度表達與子宮內膜癌預後不良有關 (Balmer et al., 2006)。RAC3 是 ARHGAP6 的一個靶標,其充當宮頸癌的腫瘤抑制因數 (Li et al., 2015b)。RAC3 參與細胞骨架的組織、細胞遷移和侵襲 (Liu et al., 2015c)。RAC3 在白血病和非小細胞肺癌中差異表達,並參與腫瘤的生長(Tan and Chen, 2014; Liu et al., 2015c; Koldehoff et al., 2008)。RAC3 在食管癌中參與 E-鈣黏蛋白的 TGF-β 誘導的下調 (Dong et al., 2014; Xu et al., 2007)。Rac3 誘導觸發乳腺癌細胞侵襲性的 Rac3/ERK-2/NF-κB 信號通路。內源性 Rac 活性與乳腺癌細胞中的高轉移相關 (Gest et al., 2013; Baugher et al., 2005)。RAC3 在數種癌症(包括白血病、攝護腺癌和乳腺癌)中上調 (Fernandez Larrosa et al., 2012; Liu et al., 2015c; Culig and Bartsch, 2006; Calaf and Roy, 2007; Engers et al., 2007; Colo et al., 2007a; Colo et al., 2007b)。RAC3 是一種 NF-κB 共啟動因數,其調節細胞週期蛋白 D1 的表達 (Rubio et al., 2012; Colo et al., 2007b)。RAC3 在 ER α 陽性乳腺癌中過度表達導致細胞遷移增強 (Walker et al., 2011; Rubio et al., 2006)。RAC3 encodes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP-binding protein Rac3), a GTPase belonging to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate diverse cellular activities, including control of cell growth, cytoskeletal reorganization, and initiation of protein kinases (RefSeq, 2002). Overexpression of RAC3 is associated with poor prognosis in endometrial cancer (Balmer et al., 2006). RAC3 is a target of ARHGAP6, which acts as a tumor suppressor in cervical cancer (Li et al., 2015b). RAC3 is involved in cytoskeleton organization, cell migration and invasion (Liu et al., 2015c). RAC3 is differentially expressed in leukemia and non-small cell lung cancer and is involved in tumor growth (Tan and Chen, 2014; Liu et al., 2015c; Koldehoff et al., 2008). RAC3 is involved in TGF-β-induced downregulation of E-cadherin in esophageal cancer (Dong et al., 2014; Xu et al., 2007). Rac3 induces the Rac3/ERK-2/NF-κB signaling pathway that triggers breast cancer cell invasiveness. Endogenous Rac activity is associated with high metastasis in breast cancer cells (Gest et al., 2013; Baugher et al., 2005). RAC3 is upregulated in several cancers, including leukemia, prostate and breast cancer (Fernandez Larrosa et al., 2012; Liu et al., 2015c; Culig and Bartsch, 2006; Calaf and Roy, 2007; Engers et al. ., 2007; Colo et al., 2007a; Colo et al., 2007b). RAC3 is a NF-κB co-initiator that regulates the expression of cyclin D1 (Rubio et al., 2012; Colo et al., 2007b). Overexpression of RAC3 in ERα-positive breast cancer results in enhanced cell migration (Walker et al., 2011; Rubio et al., 2006).
RAD54 編碼屬於DEAD 樣解旋酶家族的一種蛋白質。釀酒酵母 RAD54 和 RDH54 具有相似性,兩者均參與 DNA 同源重組和修復。該蛋白結合至雙鏈 DNA,並在存在 DNA 時顯示 ATP 酶活性。該基因在睾丸和脾臟中高度表達,這表明在減數分裂和有絲分裂重組中具有活性作用 (RefSeq, 2002)。在原發性淋巴瘤和結腸癌中觀察到了 RAD54B 的純合突變 (Hiramoto et al., 1999)。RAD54B 抵消了人類腫瘤細胞中 RAD51 直接結合至 dsDNA 的基因組不穩定影響 (Mason et al., 2015)。RAD54 encodes a protein belonging to the DEAD-like helicase family. Saccharomyces cerevisiae RAD54 and RDH54 share similarities, both involved in DNA homologous recombination and repair. This protein binds to double-stranded DNA and displays ATPase activity in the presence of DNA. This gene is highly expressed in testis and spleen, suggesting an active role in meiotic and mitotic recombination (RefSeq, 2002). Homozygous mutations in RAD54B have been observed in primary lymphoma and colon cancer (Hiramoto et al., 1999). RAD54B counteracts the genomic destabilizing effect of RAD51 binding directly to dsDNA in human tumor cells (Mason et al., 2015).
RAI14(也稱為 NORPEG)編碼視黃酸誘導 14。該基因在視網膜色素上皮細胞中檢測到,在人組織中普遍表達的全反式-視黃酸可誘導,可能在人睾丸發育和精子發生中發揮作用 (Kutty et al., 2001; Yuan et al., 2005)。RAI14 在胃癌中失調,並與細胞增殖相關。它是肺癌和乳腺癌患者的無復發生存的預後標誌物 (Zhou et al., 2015a; Hsu et al., 2013)。RAI14 (also known as NORPEG) encodes retinoic acid-induced 14. This gene was detected in retinal pigment epithelial cells, inducible by all-trans-retinoic acid ubiquitously expressed in human tissues, and may play a role in human testis development and spermatogenesis (Kutty et al., 2001; Yuan et al. ., 2005). RAI14 is dysregulated in gastric cancer and is associated with cell proliferation. It is a prognostic marker of recurrence-free survival in lung and breast cancer patients (Zhou et al., 2015a; Hsu et al., 2013).
RBM19 編碼包含六個 RNA 結合基序的核仁蛋白,並且可能參與核糖體生物合成 (RefSeq, 2002)。RBM19 在人結直腸癌中廣泛表達 (Lorenzen et al., 2005)。RBM19 突變失活在小鼠中導致 p53 活性升高和細胞凋亡增加 (Zhang et al., 2008; Deisenroth and Zhang, 2010)。RBM19 encodes a nucleolar protein containing six RNA-binding motifs and may be involved in ribosome biosynthesis (RefSeq, 2002). RBM19 is widely expressed in human colorectal cancer (Lorenzen et al., 2005). Mutational inactivation of RBM19 results in elevated p53 activity and increased apoptosis in mice (Zhang et al., 2008; Deisenroth and Zhang, 2010).
RPF1(也稱為 BXDC5)編碼包含一個 Σ (70) 樣基序以及核糖體生物合成所需的核仁 RNA 結合蛋白 (Wehner and Baserga, 2002)。RPF1 (also known as BXDC5) encodes a nucleolar RNA-binding protein that contains a Σ(70)-like motif and is required for ribosome biosynthesis (Wehner and Baserga, 2002).
RPL13A 編碼核糖體蛋白 L13P 家族的一員,其是 60S 核糖體亞基的一個組成部分。所編碼的蛋白還作為翻譯 IFN-γ 啟動抑制劑 (GAIT) 複合體的一個組成部分而在抑制炎症基因中發揮作用 (RefSeq, 2002)。RPL13A 在不同癌症類型(包括攝護腺癌、肝癌和結直腸癌)中失調 (Kasai et al., 2003; Ohl et al., 2005; Yoon et al., 2006)。RPL13A 耗竭導致核糖體 RNA 甲基化以及衍生自 p27、p53 和 SNAT2 mRNA 的IRES 元素介導的帽非依賴性翻譯顯著減少 (Chaudhuri et al., 2007)。RPL13A encodes a member of the L13P family of ribosomal proteins, which is a component of the 60S ribosomal subunit. The encoded protein also functions in suppressing inflammatory genes as a component of the translational IFN-γ initiation inhibitor (GAIT) complex (RefSeq, 2002). RPL13A is dysregulated in different cancer types, including prostate, liver, and colorectal cancer (Kasai et al., 2003; Ohl et al., 2005; Yoon et al., 2006). RPL13A depletion resulted in a marked reduction in ribosomal RNA methylation and cap-independent translation mediated by IRES elements derived from p27, p53 and SNAT2 mRNAs (Chaudhuri et al., 2007).
RPL13AP20 編碼核糖體蛋白 L13a 假基因,其位於染色體 12p13.1 上 (Balasubramanian et al., 2009)。RPL13AP20 encodes the ribosomal protein L13a pseudogene, which is located on chromosome 12p13.1 (Balasubramanian et al., 2009).
RPL13AP5 編碼核糖體蛋白 L13a 假基因,其位於染色體 10q24.1 上 (Balasubramanian et al., 2009)。RPL13AP5 encodes the ribosomal protein L13a pseudogene, which is located on chromosome 10q24.1 (Balasubramanian et al., 2009).
RPL34 編碼核糖體蛋白 L34,其是 60S 亞基的組成部分。該基因的過度表達已在某些癌細胞中觀察到 (RefSeq, 2002)。RPL34 過度表達可促進非小細胞肺癌的惡性增殖 (Yang et al., 2016)。RPL34 在細胞增殖、細胞週期分佈和人胃惡性細胞凋亡中起著關鍵作用 (Liu et al., 2015a)。RPL34 encodes the ribosomal protein L34, which is part of the 60S subunit. Overexpression of this gene has been observed in some cancer cells (RefSeq, 2002). Overexpression of RPL34 promotes the malignant proliferation of non-small cell lung cancer (Yang et al., 2016). RPL34 plays a key role in cell proliferation, cell cycle distribution and apoptosis in human gastric malignant cells (Liu et al., 2015a).
RPTOR(也稱為 RAPTOR)編碼 mTOR 調控相關蛋白,複合體 1。該蛋白是調節細胞生長以響應營養素和胰島素水準的信號傳導途徑的一個隔室。蛋白質正調節下游效應核糖體蛋白 S6 激酶,並負調節 mTOR 激酶 (RefSeq, 2002)。在無結節性硬化症複合體 1 或 2 時,mTOR-RPTOR 信令被組成性啟動,從而增強和去調節蛋白合成和細胞生長 (Avruch et al., 2005; Kwiatkowski and Manning, 2005)。 mTOR 主要透過與 RPTOR 直接相互作用而正向調節細胞生長和存活 (Sun, 2013)。與 mTOR 絡合時,RPTOR 控制帽依賴性翻譯,並且此功能對 PI3K 啟動的腫瘤發生是必要的 (Vogt et al., 2010)。雷帕黴素和類似物是主要抑制 mTOR-RPTOR 複合體 1(mTORC1,雷帕黴素敏感型)的藥物,用於乳腺癌治療 (Wysocki, 2009; De et al., 2013; Vinayak and Carlson, 2013; Le et al., 2008)。RPTOR (also known as RAPTOR) encodes the mTOR regulation-associated protein, complex 1. This protein is a compartment of a signaling pathway that regulates cell growth in response to nutrient and insulin levels. The protein positively regulates the downstream effector ribosomal protein S6 kinase and negatively regulates the mTOR kinase (RefSeq, 2002). In the absence of
SEC24D 編碼 SEC24 同源物 D,COPII 套體複合體組件。SEC24D 與 COPII 的酵母 Sec24p 組成部分具有相似性。COPII 是負責囊泡從 ER 出芽的外殼蛋白複合體。該基因產物牽涉囊泡的形成,也牽涉運輸物的選擇和濃度。這種基因突變與 Cole-Carpenter 徵候群(一種影響骨形成的病症)有關,導致顱面畸形和骨骼容易折斷 (RefSeq, 2002)。SEC24D 的誘導比在人攝護腺癌細胞系 LNCaP 中增加 (DePrimo et al., 2002; Zhao et al., 2004)。SEC24D 可透過 Akt 被磷酸化 (Sharpe et al., 2011)。SEC24D encodes SEC24 homolog D, a component of the COPII mantle complex. SEC24D shares similarity with the yeast Sec24p component of COPII. COPII is a coat protein complex responsible for vesicle budding from the ER. This gene product is involved in the formation of vesicles and also in the selection and concentration of transporters. Mutations in this gene are associated with Cole-Carpenter syndrome, a condition that affects bone formation, resulting in craniofacial deformities and bones that break easily (RefSeq, 2002). The induction ratio of SEC24D was increased in the human prostate cancer cell line LNCaP (DePrimo et al., 2002; Zhao et al., 2004). SEC24D is phosphorylated by Akt (Sharpe et al., 2011).
SEPT10 編碼單絲形成骨架 GTP 酶 septin 家族的一員。它位於細胞質和細胞核,顯示具有 GTP 結合和 GTP 酶活性 (RefSeq, 2002)。SEPT10 在不同癌症類型,包括膀胱癌、乳腺癌、肝癌、肺癌、胰腺癌和攝護腺癌以及惡性黑色素瘤和白血病中下調。它與生存不良預後相關 (Kienle et al., 2010; Liu et al., 2010b)。SEPT10 encodes a member of the septin family of monofilament-forming backbone GTPases. It is located in the cytoplasm and nucleus and has been shown to have GTP binding and GTPase activity (RefSeq, 2002). SEPT10 is downregulated in different cancer types, including bladder, breast, liver, lung, pancreatic and prostate cancers, as well as malignant melanoma and leukemia. It is associated with poor survival prognosis (Kienle et al., 2010; Liu et al., 2010b).
SEPT11 編碼參與各種細胞功能(包括細胞分裂和囊泡運輸)的單絲形成骨架 GTP 酶保守 septin 家族的一員 (RefSeq, 2002)。SEPT11 在不同癌症實體,包括腦癌、宮頸癌、胰腺癌、攝護腺癌、黑色素瘤、白血病中過度表達 (Liu et al., 2010b)。SEPT11 的雜合性丟失 (LOH) 與肝細胞癌預後差有關。與 MLL 的融合轉錄物已在骨髓瘤中發現 (Huang et al., 2010; Cerveira et al., 2011)。SEPT11 encodes a member of the conserved septin family of monofilament-forming backbone GTPases involved in various cellular functions, including cell division and vesicle trafficking (RefSeq, 2002). SEPT11 is overexpressed in different cancer entities including brain, cervical, pancreatic, prostate, melanoma, leukemia (Liu et al., 2010b). Loss of heterozygosity (LOH) of SEPT11 is associated with poor prognosis in hepatocellular carcinoma. Fusion transcripts with MLL have been found in myeloma (Huang et al., 2010; Cerveira et al., 2011).
SEPT8編碼核苷酸結合蛋白 septin 家族的一員,其高度保守,並在細胞骨架組織和胞質分裂調節中發揮作用 (RefSeq, 2002)。SEPT8在不同癌症類型,包括膀胱癌、肝癌、胰腺癌、肺癌以及白血病中上調 (Liu et al., 2010b)。SEPT8 encodes a member of the septin family of nucleotide-binding proteins that is highly conserved and plays a role in cytoskeletal organization and cytokinesis regulation (RefSeq, 2002). SEPT8 is upregulated in different cancer types, including bladder, liver, pancreatic, lung, and leukemia (Liu et al., 2010b).
SERPINB2(也稱為 PAI2)編碼絲氨酸蛋白酶抑制劑,分化體 B(卵清蛋白),成員2,位於染色體 18q21.3 上。它是一種非傳統的絲氨酸蛋白酶抑制劑 (SERPIN),其影響基因表達、細胞增殖和分化以及凋亡 (RefSeq, 2002; Medcalf and Stasinopoulos, 2005)。SERPINB2 編碼絲氨酸蛋白酶抑制劑,分化體 B(卵清蛋白)成員 2,這是一種胞外蛋白酶尿激酶纖溶酶原啟動物和組織纖維蛋白溶酶原啟動物的抑制劑 (Schroder et al., 2014)。SERPINB2 在許多不同的腫瘤中表達。SERPINB2 表達與乳腺癌和胰腺癌預後良好有關,但與子宮內膜癌、卵巢癌和結直腸癌的預後不良有關 (Schroder et al., 2014)。SERPINB2 是一種侵襲和轉移相關基因 (Pucci et al., 2016)。SERPINB2 調節尿激酶型纖溶酶原啟動劑 (uPA),其觸發纖溶酶原至纖溶酶的轉換。纖溶酶能夠降解細胞外基質 (ECM),這是腫瘤進展的一個重要過程 (Gershtein and Kushlinskii, 1999; Ulisse et al., 2009; Berger, 2002; Baldini et al., 2012; Mekkawy et al., 2014; Andreasen et al., 2000)。ECM 降解導致腫瘤進展、腫瘤大量擴展、腫瘤生長因數釋放、細胞因數活化、腫瘤細胞增殖、遷移和侵襲 (Hildenbrand et al., 2010; Magdolen et al., 2003; Halamkova et al., 2012; Duffy, 2004; Mekkawy et al., 2014; Dass et al., 2008)。許多腫瘤顯示 uPA 系統元件與腫瘤侵襲性和存活之間存在相關性 (Mekkawy et al., 2014; Duffy and Duggan, 2004; Han et al., 2005)。高水準 SERPINB2 減少腫瘤生長和轉移 (Croucher et al., 2008)。SERPINB2 (also known as PAI2) encodes a serine protease inhibitor, clade B (ovalbumin), member 2, located on chromosome 18q21.3. It is a non-traditional serine protease inhibitor (SERPIN) that affects gene expression, cell proliferation and differentiation, and apoptosis (RefSeq, 2002; Medcalf and Stasinopoulos, 2005). SERPINB2 encodes a serine protease inhibitor, clade B (ovalbumin) member 2, an inhibitor of the extracellular proteases urokinase plasminogen promoter and tissue plasminogen promoter (Schroder et al., 2014). SERPINB2 is expressed in many different tumors. SERPINB2 expression is associated with good prognosis in breast and pancreatic cancer, but poor prognosis in endometrial, ovarian, and colorectal cancers (Schroder et al., 2014). SERPINB2 is an invasion and metastasis-related gene (Pucci et al., 2016). SERPINB2 regulates urokinase-type plasminogen initiator (uPA), which triggers the conversion of plasminogen to plasmin. Plasmin degrades the extracellular matrix (ECM), an important process in tumor progression (Gershtein and Kushlinskii, 1999; Ulisse et al., 2009; Berger, 2002; Baldini et al., 2012; Mekkawy et al., 2014; Andreasen et al., 2000). ECM degradation leads to tumor progression, massive tumor expansion, tumor growth factor release, cytokine activation, tumor cell proliferation, migration and invasion (Hildenbrand et al., 2010; Magdolen et al., 2003; Halamkova et al., 2012; Duffy, 2004; Mekkawy et al., 2014; Dass et al., 2008). Numerous tumors have shown a correlation between elements of the uPA system and tumor aggressiveness and survival (Mekkawy et al., 2014; Duffy and Duggan, 2004; Han et al., 2005). High levels of SERPINB2 reduce tumor growth and metastasis (Croucher et al., 2008).
SH3BP4 編碼 SH3 結構域結合蛋白 4,其參與網格蛋白介導的內吞作用的運輸特定控制,具體來說是特定蛋白受體的內化控制 (RefSeq, 2002)。SH3BP4 表達在成視網膜細胞瘤細胞系 Y79 增加 7 倍 (Khanobdee et al., 2004)。SH3BP4 耗盡細胞中的成纖維細胞生長因數受體 10 刺激導致乳腺癌細胞中細胞遷移減少以及小鼠肺外植體上皮分枝的抑制 (Francavilla et al., 2013)。SH3BP4 encodes SH3 domain-binding protein 4, which is involved in the transport-specific control of clathrin-mediated endocytosis, specifically the internalization control of specific protein receptors (RefSeq, 2002). SH3BP4 expression was increased 7-fold in the retinoblastoma cell line Y79 (Khanobdee et al., 2004). Fibroblast
SHCBP1 編碼與人類中樞紡錘體蛋白相關的一種蛋白,是參與中間體組織和胞質分裂完成的關鍵因素之一 (Asano et al., 2014)。SHCBP1 在人肝細胞癌中上調。靶向作用於 SHCBP1 抑制肝細胞癌細胞系增殖 (Tao et al., 2013)。在具有伴隨基因組改變的 16 個基因中,SHCBP1 可能參與腫瘤發生以及侵襲和從侵襲前導管原位癌進展到浸潤性導管癌的過程 (Colak et al., 2013)。SHCBP1 encodes a protein related to the human central spindle protein and is one of the key factors involved in the organization of intermediates and completion of cytokinesis (Asano et al., 2014). SHCBP1 is upregulated in human hepatocellular carcinoma. Targeting SHCBP1 inhibits proliferation of hepatocellular carcinoma cell lines (Tao et al., 2013). Among 16 genes with concomitant genomic alterations, SHCBP1 may be involved in tumorigenesis as well as invasion and progression from preinvasive ductal carcinoma in situ to invasive ductal carcinoma (Colak et al., 2013).
SIGMAR1(也稱為 OPRS1 或 SIG-1R)編碼一種與多種精神病藥物(包括可卡因和安非他明)相互作用的 Σ 非阿片類細胞內受體。這種基因的突變與少年肌萎縮性側索硬化症相關 (RefSeq, 2002)。SIGMAR1 在腫瘤細胞系以及各種癌組織的腫瘤(包括肺癌、結腸癌、皮膚癌和乳腺癌)中過度表達。SIGMAR1 過度表達與細胞增殖相關(Vilner et al., 1995; Aydar et al., 2004; Aydar et al., 2006; Bem et al., 1991; Skrzycki and Czeczot, 2013)。SIGMAR1 促進 hERG/bet1 整聯蛋白信令,觸發 PI3K/Akt 通路的啟動,並誘導翻譯調節蛋白樣 p70S6K、S6 和 4E-BP1 的磷酸化。SIGMAR1 增加運動性和 VEGF 分泌,從而提高腫瘤細胞的侵襲性 (Crottes et al., 2016; Kim et al., 2012a)。SIGMAR1 (also known as OPRS1 or SIG-1R) encodes a Σ non-opioid intracellular receptor that interacts with several psychiatric drugs, including cocaine and amphetamines. Mutations in this gene are associated with juvenile amyotrophic lateral sclerosis (RefSeq, 2002). SIGMAR1 is overexpressed in tumor cell lines as well as in tumors of various cancer tissues, including lung, colon, skin, and breast cancer. SIGMAR1 overexpression is associated with cell proliferation (Vilner et al., 1995; Aydar et al., 2004; Aydar et al., 2006; Bem et al., 1991; Skrzycki and Czeczot, 2013). SIGMAR1 promotes hERG/bet1 integrin signaling, triggers initiation of the PI3K/Akt pathway, and induces phosphorylation of translational regulatory proteins like p70S6K, S6, and 4E-BP1. SIGMAR1 increases motility and VEGF secretion, thereby increasing tumor cell invasiveness (Crottes et al., 2016; Kim et al., 2012a).
SLC16A3 編碼溶質載體家族 16 成員 3,這是一種質子連接的單羧酸轉運蛋白 (RefSeq, 2002)。已知大多數實體瘤依靠糖酵解產生能量。高糖酵解率導致乳酸產生增加,這與不良臨床結果有關,並直接有助於腫瘤生長和進展。SLC16A3 是其促進癌細胞乳酸輸出的少數單羧酸轉運蛋白之一 (Dhup et al., 2012; Draoui and Feron, 2011)。SLC16A3 表達與肝細胞癌患者較差預後有關,在細胞系實驗中,可增加細胞增殖、遷移和侵襲 (Gao et al., 2015)。在胰腺癌子集中,SLC16A3 顯示在腫瘤發生中有功能性參與 (Baek et al., 2014)。SLC16A3 encodes solute carrier family 16
SLC1A4(也稱為 ASCT1)編碼溶質載體家族(谷氨酸/中性氨基酸轉運體),成員 4,其位於染色體 2p15-p13 上 (RefSeq, 2002)。肝細胞癌細胞系 C3A 在半胱氨酸喪失後增強 SLC1A4 的表達 (Lee et al., 2008b)。SLC1A4 在食管腺癌中充當氨基酸的募集因數 (Younes et al., 2000)。人肝癌細胞中 ASCT2 的敲除提高了 SLC1A4 mRNA 水準 (Fuchs et al., 2004)。v-myc 髓細胞增生病毒癌基因同源基因的活化導致人腦膠質瘤細胞系 Hs683 中 SLC1A4 的上調 (Jiang et al., 2012)。穀氨醯胺喪失不會導致神經母細胞瘤中 SLC1A4 的上調 (Wasa et al., 2002)。SLC1A4 (also known as ASCT1) encodes a family of solute carriers (glutamate/neutral amino acid transporters), member 4, which is located on chromosomes 2p15-p13 (RefSeq, 2002). The hepatocellular carcinoma cell line C3A enhanced the expression of SLC1A4 following cysteine loss (Lee et al., 2008b). SLC1A4 acts as an amino acid recruitment factor in esophageal adenocarcinoma (Younes et al., 2000). Knockdown of ASCT2 in human hepatoma cells increased SLC1A4 mRNA levels (Fuchs et al., 2004). Activation of the v-myc myeloproliferation virus oncogene homologue leads to upregulation of SLC1A4 in the human glioma cell line Hs683 (Jiang et al., 2012). Loss of glutamine does not result in upregulation of SLC1A4 in neuroblastoma (Wasa et al., 2002).
SLC1A5(也稱為 ASCT2)編碼溶質載體家族(谷氨酸/中性氨基酸轉運體),成員 5,這是可充當 RD114/D 型逆轉錄病毒的受體的一個鈉依賴性中性氨基酸轉運蛋白 (RefSeq, 2002)。c-Myc 啟動增加 SLC1A5 表達 (Perez-Escuredo et al., 2016)。SLC1A5 過度表達與透明細胞腎細胞癌的預後不良相關 (Liu et al., 2015d)。CD147 的高表達與胰腺癌患者的 SLC1A5 顯著相關 (Kaira et al., 2015)。SLC1A5 可能是非小細胞肺癌的一種生物標誌物 (Hassanein et al., 2015; Hassanein et al., 2016)。泛素連接酶 RNF5 調節乳腺癌的 SLC1A5 (Jeon et al., 2015)。SLC1A5 在幾個腫瘤實體,包括晚期喉癌、攝護腺癌和腺樣囊性癌中過度表達 (Koo and Yoon, 2015; Wang et al., 2015f; Bhutia et al., 2015; Nikkuni et al., 2015; Ganapathy et al., 2009)。乳腺癌中 SLC1A5 的抑制導致穀氨醯胺攝取和增殖下降 (Chen et al., 2015d; van et al., 2015)。SLC1A5 可透過調節 mTOR 刺激腫瘤生長 (Nakanishi and Tamai, 2011; Fuchs and Bode, 2005; Corbet et al., 2016; McGivan and Bungard, 2007)。SLC1A5 (also known as ASCT2) encodes the solute carrier family (glutamate/neutral amino acid transporter),
SLC26A6 編碼溶質載體家族 26 的一員,該家族包含陰離子轉運蛋白。SLC26A6 參與運送氯化物、草酸鹽、硫酸鹽和碳酸氫根離子 (RefSeq, 2002)。SLC26A6 的突變已在不同的結直腸癌細胞系中得到確認 (Donnard et al., 2014)。SLC26A6 基因表達和啟動子活性受 IFN-γ 抑制 (Saksena et al., 2010)。SLC26A6 encodes a member of the solute carrier family 26, which contains anion transporters. SLC26A6 is involved in the transport of chloride, oxalate, sulfate and bicarbonate ions (RefSeq, 2002). Mutations in SLC26A6 have been identified in different colorectal cancer cell lines (Donnard et al., 2014). SLC26A6 gene expression and promoter activity were inhibited by IFN-γ (Saksena et al., 2010).
SLC52A3(也稱為 RFT2 或 C20orf54)編碼溶質載體家族 52 的一員。它是一個核黃素轉運蛋白,可能在核黃素腸道吸收中起作用 (RefSeq, 2002)。SLC52A3 在不同癌症實體,包括胃癌、食管鱗狀細胞癌和宮頸癌中失調。SLC52A3 的單核苷酸多態性與食管鱗狀細胞癌及賁門腺癌的癌症風險相關 (Jiang et al., 2014b; Duan et al., 2015; Matnuri et al., 2015; Eli et al., 2012; Aili et al., 2013)。SLC52A3 敲除增加 p21 和 p27 的蛋白水準並減少其下游靶向細胞週期蛋白 E1 和 Cdk2,導致細胞週期停滯在 G1-G1/S 期。SLC52A3 敲除還導致半胱天冬酶-3 和 細胞凋亡的啟動 (Jiang et al., 2014b)。SLC52A3 (also known as RFT2 or C20orf54) encodes a member of the solute carrier family 52. It is a riboflavin transporter and may play a role in the intestinal absorption of riboflavin (RefSeq, 2002). SLC52A3 is dysregulated in different cancer entities including gastric, esophageal squamous cell carcinoma and cervical cancer. A single nucleotide polymorphism of SLC52A3 is associated with cancer risk in esophageal squamous cell carcinoma and cardiac adenocarcinoma (Jiang et al., 2014b; Duan et al., 2015; Matnuri et al., 2015; Eli et al., 2012; Aili et al., 2013). Knockdown of SLC52A3 increases the protein levels of p21 and p27 and reduces their downstream targeting of cyclins E1 and Cdk2, resulting in cell cycle arrest in the G1-G1/S phase. Knockout of SLC52A3 also resulted in the initiation of caspase-3 and apoptosis (Jiang et al., 2014b).
SLC6A15 編碼溶質載體家族 6 的一員,其轉運中性氨基酸。SLC6A15 可能在神經元氨基酸轉運中起作用,並可能與重性抑鬱症相關 (RefSeq, 2002)。SLC6A15 被超甲基化從而在結直腸癌中下調,可能是基於糞便測定法的候選生物標誌物 (Kim et al., 2011b; Mitchell et al., 2014)。SLC6A15 encodes a member of solute carrier family 6 that transports neutral amino acids. SLC6A15 may play a role in neuronal amino acid transport and may be associated with major depression (RefSeq, 2002). SLC6A15 is hypermethylated and downregulated in colorectal cancer and may be a candidate biomarker based on stool assays (Kim et al., 2011b; Mitchell et al., 2014).
SMIM10 (也稱為 CXorf69 或 LOC644538)編碼位於染色體 Xq26.3 上的小整合膜蛋白 (RefSeq, 2002)。SMIM10 (also known as CXorf69 or LOC644538) encodes a small integral membrane protein located on chromosome Xq26.3 (RefSeq, 2002).
SNX14 編碼分揀連接蛋白家族的一員,並含有 G 蛋白信號 (RGS) 結構域調節因數 (RefSeq, 2002)。SNX14 在小鼠胚胎成纖維細胞 rasV12/E1A 轉換後下調,並且可能與腫瘤發展有關 (Vasseur et al., 2005)。SNX14 encodes a member of the Sortil junction protein family and contains a G protein signaling (RGS) domain regulator (RefSeq, 2002). SNX14 is downregulated after rasV12/E1A transition in mouse embryonic fibroblasts and may be involved in tumor development (Vasseur et al., 2005).
SSH1(也稱為 SSH1L)編碼磷酸酶彈弓同源物 (SSH) 家族的一員。SSH 家族似乎透過重新啟動絲切蛋白在肌動蛋白動力學中發揮作用 (RefSeq, 2002)。SSH1 在胰腺癌中過度表達,與腫瘤細胞的遷移有關 (Wang et al., 2015k)。透過神經調節蛋白抑制 PKD1 導致 SSH1 位於 F-肌動蛋白、增加絲切蛋白活性並增強細胞骨架和細胞遷移的重組。絲切蛋白的 SSH1 依賴性啟動由 PI3K/Akt 信號途徑誘導 (Wang et al., 2010; Doppler et al., 2013)。SSH1 (also known as SSH1L) encodes a member of the slingshot homolog (SSH) family of phosphatase enzymes. The SSH family appears to play a role in actin dynamics by reactivating cofilin (RefSeq, 2002). SSH1 is overexpressed in pancreatic cancer and has been implicated in tumor cell migration (Wang et al., 2015k). Inhibition of PKD1 via neuregulin results in SSH1 localization to F-actin, increased cofilin activity, and enhanced reorganization of the cytoskeleton and cell migration. SSH1-dependent initiation of cofilin is induced by the PI3K/Akt signaling pathway (Wang et al., 2010; Doppler et al., 2013).
STAT2 在干擾素引發的轉錄啟動響應中作為一個正調節因數 (Steen and Gamero, 2012)。STAT2 可調節對干擾素的腫瘤細胞應答 (Shodeinde et al., 2013)。在大腦中缺乏 STAT2 (Yue et al., 2015) 或組成性表達 IFN-α (Wang et al., 2003) 的轉基因小鼠中觀察到了 STAT2 與腫瘤發生之間的聯繫。STAT2 acts as a positive regulator in interferon-triggered transcriptional initiation responses (Steen and Gamero, 2012). STAT2 regulates tumor cell responses to interferons (Shodeinde et al., 2013). The link between STAT2 and tumorigenesis has been observed in transgenic mice lacking STAT2 (Yue et al., 2015) or constitutively expressing IFN-α (Wang et al., 2003) in the brain.
SUPT16H 編碼 FACT(促進染色質轉錄)的一個亞基,這是包裝至染色質的 DNA 轉錄所需要的輔助因數 (RefSeq, 2002)。SUPT16H 在鼻咽血管纖維瘤 (JNA) 的內皮細胞和間質成分中被失調,並可能由此作為一個潛在的分子標誌物發揮作用 (Silveira et al., 2012)。SUPT16H 透過染色質重塑參與 DNA 雙鏈斷裂修復。SUPT16H 透過與 CK2 形成一個複合體啟動 p53 (Keller et al., 2001; Kari et al., 2011)。SUPT16H encodes a subunit of FACT (Facilitates Chromatin Transcription), a cofactor required for transcription of DNA packaged into chromatin (RefSeq, 2002). SUPT16H is dysregulated in the endothelial and stromal components of nasopharyngeal angiofibromas (JNA) and may thus function as a potential molecular marker (Silveira et al., 2012). SUPT16H is involved in DNA double-strand break repair through chromatin remodeling. SUPT16H activates p53 by forming a complex with CK2 (Keller et al., 2001; Kari et al., 2011).
SUSD1 編碼含有 sushi 結構域的蛋白,並與靜脈血栓栓塞風險增加相關 (Tang et al., 2013)。雜合 SUSD1-ROD1/PTBP3 融合轉錄物在人乳腺癌細胞系中表達 (Newman et al., 2013)。SUSD1 encodes a sushi domain-containing protein and is associated with an increased risk of venous thromboembolism (Tang et al., 2013). A hybrid SUSD1-ROD1/PTBP3 fusion transcript is expressed in a human breast cancer cell line (Newman et al., 2013).
TAF6L 編碼與組蛋白樣 TATA 盒結合蛋白相關因數 6 (TAF6) 結構相似的蛋白。它是 PCAF 組蛋白乙醯化酶複合體的一個組成部分,是生肌轉錄和分化所需的 (RefSeq, 2002)。miR-145 和 miR-196A 的表達與 TAF6L 的表達呈負相關 (Havelange et al., 2011)。TAF6L 在小細胞肺癌細胞系 H187 中透過形成融合轉錄物 TAF6L-GNG3 而被滅活 (Fernandez-Cuesta et al., 2015)。TAF6L encodes a protein that is structurally similar to histone-like TATA box-binding protein-associated factor 6 (TAF6). It is a component of the PCAF histone acetylase complex and is required for myogenic transcription and differentiation (RefSeq, 2002). The expression of miR-145 and miR-196A was inversely correlated with the expression of TAF6L (Havelange et al., 2011). TAF6L is inactivated in the small cell lung cancer cell line H187 by forming the fusion transcript TAF6L-GNG3 (Fernandez-Cuesta et al., 2015).
TEP1 編碼端粒酶相關蛋白 1,它是負責端粒酶活性的核糖核蛋白複合體的一個組成部分,其催化在染色體末端上增加新的端粒 (RefSeq, 2002; Szaflarski et al., 2011)。TEP1 是拱頂蛋白的主要部分,主要的拱頂蛋白 (MVP) 也屬於該拱頂蛋白 (Lara et al., 2011; Mossink et al., 2003)。TEP1 在甲狀腺癌中表達 (Hoang-Vu et al., 2002)。TEP1 encodes telomerase-associated
TFPI 編碼組織因數途徑抑制劑,這是調節凝血的組織因數 (TF) 依賴性途徑的一種蛋白酶抑制劑 (RefSeq, 2002)。TFPI 在乳腺癌、結直腸癌和胰腺癌細胞系中表達 (Kurer, 2007)。TFPI 在乳腺癌中誘導 HIF1α、c-Myc、c-SRC 和 HDAC2 (Davies et al., 2014)。與非惡性病變相比,TFPI 表達水準在肉瘤中降低 (Savitskaya et al., 2012)。TFPI 抑制 TF-VIIa 複合體的蛋白酶活性,其參與轉移 (Fischer et al., 1999; Sandset and Abildgaard, 1991; Lindahl et al., 1991)。TFPI encodes tissue factor pathway inhibitor, a protease inhibitor of the tissue factor (TF)-dependent pathway that regulates coagulation (RefSeq, 2002). TFPI is expressed in breast, colorectal, and pancreatic cancer cell lines (Kurer, 2007). TFPI induces HIF1α, c-Myc, c-SRC and HDAC2 in breast cancer (Davies et al., 2014). TFPI expression levels are reduced in sarcomas compared to non-malignant lesions (Savitskaya et al., 2012). TFPI inhibits the protease activity of the TF-VIIa complex, which is involved in metastasis (Fischer et al., 1999; Sandset and Abildgaard, 1991; Lindahl et al., 1991).
TFPI2 編碼組織因數途徑抑制物 2,其能抑制多種絲氨酸蛋白酶,包括凝血因數 VIIa/組織因數、因數 Xa、纖溶酶、胰蛋白酶、胰凝乳蛋白酶和血漿激肽釋放酶。該基因在幾種癌症類型中被確定為腫瘤抑制基因 (RefSeq, 2002; Sierko et al., 2007)。TFPI2 可作為胰腺癌復發預測的一種生物標誌物 (Zhai et al., 2015c)。TFPI2 的 DNA 甲基化在糞便潛血檢查可用作結直腸癌的一種生物標誌物 (Koga et al., 2015)。TFPI2 誘導細胞凋亡,並抑制腫瘤的侵襲、生長、轉移和血管生成 (Ghilardi et al., 2015; Amirkhosravi et al., 2007; Sierko et al., 2007)。TFPI2 在癌症中被超甲基化和下調,表達與癌症程度、早期腫瘤復發和預後不良相關 (Sun et al., 2016a; Sierko et al., 2007)。TFPI2 在胰腺癌和膽管癌中下調 (Chu et al., 2015; Zhai et al., 2015a; Zhai et al., 2015b)。 TFPI2 在胃癌、犬彌漫性大 B 細胞淋巴瘤、急性骨髓性白血病、非小細胞肺癌、宮頸癌、口腔鱗狀細胞癌、炎症相關結腸癌和肝細胞癌中被甲基化 (Qu et al., 2013; Ferraresso et al., 2014; Liu et al., 2014b; Shao et al., 2014; Lai et al., 2014; Hamamoto et al., 2015; Li et al., 2015d; Gerecke et al., 2015; Dong et al., 2015; Sun et al., 2016a)。TFPI2 是癌症中經充分驗證的 DNA 甲基化生物標誌物 (Fukushige and Horii, 2013; Huisman et al., 2015)。TFPI2 encodes tissue factor pathway inhibitor 2, which inhibits multiple serine proteases, including coagulation factor VIIa/tissue factor, factor Xa, plasmin, trypsin, chymotrypsin, and plasma kallikrein. This gene has been identified as a tumor suppressor gene in several cancer types (RefSeq, 2002; Sierko et al., 2007). TFPI2 can be used as a biomarker for predicting pancreatic cancer recurrence (Zhai et al., 2015c). DNA methylation of TFPI2 can be used as a biomarker for colorectal cancer in fecal occult blood examination (Koga et al., 2015). TFPI2 induces apoptosis and inhibits tumor invasion, growth, metastasis and angiogenesis (Ghilardi et al., 2015; Amirkhosravi et al., 2007; Sierko et al., 2007). TFPI2 is hypermethylated and downregulated in cancer, and expression correlates with cancer extent, early tumor recurrence, and poor prognosis (Sun et al., 2016a; Sierko et al., 2007). TFPI2 is downregulated in pancreatic and cholangiocarcinomas (Chu et al., 2015; Zhai et al., 2015a; Zhai et al., 2015b). TFPI2 is methylated in gastric cancer, canine diffuse large B-cell lymphoma, acute myeloid leukemia, non-small cell lung cancer, cervical cancer, oral squamous cell carcinoma, inflammation-associated colon cancer, and hepatocellular carcinoma (Qu et al. , 2013; Ferraresso et al., 2014; Liu et al., 2014b; Shao et al., 2014; Lai et al., 2014; Hamamoto et al., 2015; Li et al., 2015d; Gerecke et al., 2015; Dong et al., 2015; Sun et al., 2016a). TFPI2 is a well-validated DNA methylation biomarker in cancer (Fukushige and Horii, 2013; Huisman et al., 2015).
TGFBI 編碼含 RGD 蛋白,其結合至 I 、II 和 IV 型膠原,並由轉化生長因數-β 誘導,在細胞-膠原相互作用中發揮作用並可抑制細胞黏附 (RefSeq, 2002)。TGFBI 表達被證明在膽管癌、肝癌、胃癌、食管癌和腎透明細胞癌中升高。此外,TGFBI 被證明與結直腸癌有關 (Lebdai et al., 2015; Ozawa et al., 2014; Zhu et al., 2015a; Han et al., 2015)。TGFBI encodes an RGD-containing protein that binds to collagen types I, II and IV and is induced by transforming growth factor-β, plays a role in cell-collagen interactions and inhibits cell adhesion (RefSeq, 2002). TGFBI expression was shown to be elevated in cholangiocarcinoma, liver cancer, gastric cancer, esophageal cancer and renal clear cell carcinoma. In addition, TGFBI has been shown to be associated with colorectal cancer (Lebdai et al., 2015; Ozawa et al., 2014; Zhu et al., 2015a; Han et al., 2015).
TGIF2-C20orf24 編碼與 TGIF2 和 C20orf24 具有序列同一性的融合蛋白 (RefSeq, 2002)。TGIF2-C20orf24 encodes a fusion protein with sequence identity to TGIF2 and C20orf24 (RefSeq, 2002).
TMEM154 編碼與 2 型糖尿病風險增加相關其似乎在 β 細胞功能中發揮作用的跨膜蛋白 (Harder et al., 2015)。TMEM154 encodes a transmembrane protein that appears to play a role in beta cell function associated with an increased risk of type 2 diabetes (Harder et al., 2015).
TRAM2 編碼易位相關膜蛋白 2。它是易位子的一個組成部分,即在內質網 (ER) 膜控制初生分泌蛋白和膜蛋白的翻譯後處理的門控大分子通道 (RefSeq, 2002)。Runx2 可調節 TRAM2 表達 (Pregizer et al., 2007)。TRAM2 中的 SNP 可增加 ER 陽性乳腺癌患者的骨折風險 (Liu et al., 2014a)。TRAM2 encodes translocation-associated membrane protein 2. It is a component of the translocon, a gated macromolecular channel at the endoplasmic reticulum (ER) membrane that controls the post-translational processing of nascent secreted and membrane proteins (RefSeq, 2002). Runx2 regulates TRAM2 expression (Pregizer et al., 2007). SNPs in TRAM2 increase fracture risk in patients with ER-positive breast cancer (Liu et al., 2014a).
TRPV2 編碼被高於 52 攝氏度的溫度活化的離子通道。它可能參與感覺神經節中高溫熱回應的轉導 (RefSeq, 2002)。TRPV2 在不同癌症類型(包括食管癌、攝護腺癌、肝癌、膀胱癌和白血病)中失調。TRPV2 的損失或改變導致不受控制的增殖和凋亡刺激物的抗性 (Liberati et al., 2014a; Zhou et al., 2014; Liberati et al., 2014b; Liu et al., 2010a; Morelli et al., 2013)。神經膠質瘤細胞中 TRPV2 的沉寂導致下調 Fas 和親蛋白酶 8,以及上調細胞週期蛋白 E1、CDK2 E2F1 和 Bcl-2 相關 X 蛋白。膀胱癌細胞中 TRPV2 過度表達導致細胞遷移和侵襲增強 (Nabissi et al., 2010; Liu and Wang, 2013)。TRPV2 encodes an ion channel that is activated by temperatures above 52 degrees Celsius. It may be involved in the transduction of hyperthermic thermal responses in sensory ganglia (RefSeq, 2002). TRPV2 is dysregulated in different cancer types, including esophageal, prostate, liver, bladder, and leukemia. Loss or alteration of TRPV2 leads to uncontrolled proliferation and resistance to apoptotic stimuli (Liberati et al., 2014a; Zhou et al., 2014; Liberati et al., 2014b; Liu et al., 2010a; Morelli et al. al., 2013). Silencing of TRPV2 in glioma cells resulted in downregulation of Fas and protease 8, and upregulation of cyclin E1, CDK2 E2F1, and Bcl-2-related X protein. TRPV2 overexpression in bladder cancer cells leads to enhanced cell migration and invasion (Nabissi et al., 2010; Liu and Wang, 2013).
TSEN15 編碼 tRNA 剪接核酸內切酶亞基 15。此內切酶催化將內含子從 tRNA 前體中去除 (RefSeq, 2002; Trotta et al., 2006)。TSEN15 是 miRNA-449A 的一個靶標,其功能是作為神經母細胞瘤的腫瘤抑制因數。TSEN15 在介導 miRNA-449A 分化誘導功能中起重要作用 (Zhao et al., 2015)。TSEN15 與人胎兒股骨來源的細胞的細胞分化潛能相關 (Mirmalek-Sani et al., 2009)。TSEN15 encodes the tRNA splicing endonuclease subunit 15. This endonuclease catalyzes the removal of introns from tRNA precursors (RefSeq, 2002; Trotta et al., 2006). TSEN15 is a target of miRNA-449A that functions as a tumor suppressor in neuroblastoma. TSEN15 plays an important role in mediating the differentiation-inducing function of miRNA-449A (Zhao et al., 2015). TSEN15 is associated with the cellular differentiation potential of human fetal femur-derived cells (Mirmalek-Sani et al., 2009).
UBE2C(也稱為 UBCH10)編碼 E2 泛素結合酶家族的一員。它是有絲分裂細胞週期蛋白和細胞週期進展破壞所需要的 (RefSeq, 2002)。根據在乳腺癌、肺癌和結直腸癌患者中的觀察,UBE2C 往往透過基因擴增上調。BE2C上調與預後差和腫瘤進展相關 (Okamoto et al., 2003; Wagner et al., 2004; Fujita et al., 2009; Chen et al., 2010; Hao et al., 2012)。UBE2C 在 U251 膠質瘤細胞以及來自於結直腸癌 (CRC) 患者的組織中上調。UBE2C 敲除透過誘導 Bax 和 p53、下調 Bcl-2 和 G2/M 細胞週期阻滯而誘導細胞凋亡。UBE2C 的抑制導致 CRC 中細胞週期蛋白 B 和 ERK1 失調 (Cacciola et al., 2015; Jiang et al., 2010)。UBE2C (also known as UBCH10) encodes a member of the E2 ubiquitin-conjugating enzyme family. It is required for mitotic cyclins and disruption of cell cycle progression (RefSeq, 2002). UBE2C tends to be up-regulated through gene amplification, as observed in breast, lung, and colorectal cancer patients. Upregulation of BE2C is associated with poor prognosis and tumor progression (Okamoto et al., 2003; Wagner et al., 2004; Fujita et al., 2009; Chen et al., 2010; Hao et al., 2012). UBE2C is upregulated in U251 glioma cells and tissues from colorectal cancer (CRC) patients. UBE2C knockout induced apoptosis through induction of Bax and p53, downregulation of Bcl-2 and G2/M cell cycle arrest. Inhibition of UBE2C leads to dysregulation of cyclin B and ERK1 in CRC (Cacciola et al., 2015; Jiang et al., 2010).
UBIAD1(也稱為 TERE1)編碼包含可能參與膽固醇和磷脂代謝的 UbiA異戊烯轉移酶結構域的一個蛋白質 (RefSeq, 2002)。腫瘤抑制因數 UBIAD1 在不同癌症實體(包括膀胱癌、攝護腺癌和腎癌)中下調,並與生長調節有關 (McGarvey et al., 2001; Fredericks et al., 2011; McGarvey et al., 2003; Fredericks et al., 2013)。UBIAD1 調節生長因數相關 p42/44 MAP 激酶的磷酸化。UBIAD1 的高爾基體適當定位影響其腫瘤抑制因數活性,包括細胞凋亡 (McGarvey et al., 2005; Wang et al., 2013d)。UBIAD1 (also known as TERE1) encodes a protein containing the UbiA isopentenyltransferase domain that may be involved in cholesterol and phospholipid metabolism (RefSeq, 2002). The tumor suppressor UBIAD1 is downregulated in different cancer entities, including bladder, prostate, and kidney cancer, and has been implicated in growth regulation (McGarvey et al., 2001; Fredericks et al., 2011; McGarvey et al., 2003 ; Fredericks et al., 2013). UBIAD1 regulates phosphorylation of growth factor-related p42/44 MAP kinases. Proper Golgi localization of UBIAD1 affects its tumor suppressor activity, including apoptosis (McGarvey et al., 2005; Wang et al., 2013d).
UBR1 編碼泛素蛋白連接酶 E3 元件 N-識別子 1。它結合於底物蛋白質的不穩定 N-端殘基,並參與底物連接的多泛素鏈的形成,選擇該蛋白為泛素系統的蛋白水解通路 (RefSeq, 2002)。UBR1 表達的喪失或減少與自發 B 細胞淋巴瘤和 T 細胞急性淋巴細胞性白血病相關 (Chen et al., 2006)。UBR1 調節 MGMT(保護細胞免受烷化劑的致癌作用的 DNA 修復酶)的動態平衡 (Leng et al., 2015)。UBR1 encodes the ubiquitin protein ligase E3 element N-
UBR2 編碼 N-端規則蛋白水解途徑的 E3 泛素連接酶,靶向作用於含有不穩定 N 端殘基的蛋白以進行多泛素化以及蛋白酶體介導的降解 (RefSeq, 2002)。針對 UBR2 的自身抗體在自身免疫性胰腺炎和胰腺癌患者的血清中檢測到 (Frulloni et al., 2009)。UBR2 透過 p38beta/MAPK的啟動、C/EBPβ 的磷酸化以及結合到 UBR2 啟動子由腫瘤細胞誘導的惡病質刺激物上調 (Zhang et al., 2013b)。UBR2 encodes an E3 ubiquitin ligase of the N-terminal rule proteolytic pathway that targets proteins containing labile N-terminal residues for polyubiquitination and proteasome-mediated degradation (RefSeq, 2002). Autoantibodies against UBR2 were detected in the serum of patients with autoimmune pancreatitis and pancreatic cancer (Frulloni et al., 2009). UBR2 is upregulated by tumor cell-induced cachexia stimuli through p38beta/MAPK initiation, C/EBPβ phosphorylation, and binding to the UBR2 promoter (Zhang et al., 2013b).
URB1 是 60S 核糖體亞基早期成熟過程中核糖體合成所需的 (Rosado and de la Cruz, 2004)。URB1 is required for ribosome synthesis during early maturation of the 60S ribosomal subunit (Rosado and de la Cruz, 2004).
USP11 編碼泛素特異性肽酶 11。蛋白的泛素化控制許多細胞內過程,包括細胞週期進程、轉錄啟動和信號轉導 (RefSeq, 2002)。USP11 是 p53 的一種新型調節因數,這是 p53 活化回應於 DNA 損傷所需要的 (Ke et al., 2014a)。USP11在早幼粒細胞白血病和胰腺癌起著主要作用 (Burkhart et al., 2013; Wu et al., 2014)。USP11 encodes ubiquitin-specific peptidase 11. Ubiquitination of proteins controls many intracellular processes, including cell cycle progression, transcription initiation, and signal transduction (RefSeq, 2002). USP11 is a novel regulator of p53, which is required for p53 activation in response to DNA damage (Ke et al., 2014a). USP11 plays a major role in promyelocytic leukemia and pancreatic cancer (Burkhart et al., 2013; Wu et al., 2014).
USP22 編碼泛素特定肽酶 22,位於染色體 17p11.2上 (RefSeq, 2002)。在肝細胞癌、結腸癌、胃癌、卵巢癌、胰腺癌、神經膠質瘤、涎腺腺樣囊性癌和甲狀腺乳頭狀癌中觀察到了 USP22 高表達 (Wang et al., 2013b; Dai et al., 2014; Liang et al., 2014a; Liang et al., 2014b; Ji et al., 2015; He et al., 2015; Wang et al., 2015n; Tang et al., 2015)。USP22 促進腫瘤進展,並誘導肺腺癌上皮間質轉變 (Hu et al., 2015a)。USP22 透過調節非小細胞肺癌環氧合酶 2 的穩定性而充當致癌基因(Xiao et al., 2015)。USP22 在鼻咽癌的病理過程中起著關鍵調節作用,它可能是一種潛在的治療靶標 (Zhuang et al., 2015)。USP22 的過度表達可能有助於促進乳腺癌進展(Zhang et al., 2011)。USP22 encodes ubiquitin-
UTP20 是 U3 小核仁 RNA 蛋白複合體的組分,並參與 18s rRNA 的加工 (RefSeq, 2002)。UTP20表達在轉移性人乳腺腫瘤細胞系中降低 (Schwirzke et al., 1998; Goodison et al., 2003)。UTP20 在胃癌組織和癌前病變中高水準表達,暗示 UTP20 參與細胞轉化 (Xing et al., 2005)。UTP20 is a component of the U3 small nucleolar RNA protein complex and is involved in the processing of 18s rRNA (RefSeq, 2002). UTP20 expression is reduced in metastatic human breast tumor cell lines (Schwirzke et al., 1998; Goodison et al., 2003). UTP20 is highly expressed in gastric cancer tissues and precancerous lesions, suggesting that UTP20 is involved in cell transformation (Xing et al., 2005).
WLS(也稱為 EVI 或 GPR177)編碼 Wntless Wnt 配體分泌介導因數。WLS 代表致力於促進其分泌到細胞外環境的 Wnt 一個古老的夥伴 (Banziger et al., 2006)。WLS 在不同癌症實體(包括乳腺癌、胃癌、卵巢癌和結直腸癌以及白血病)中過度表達,並與不良預後相關 (Chiou et al., 2014; Stewart et al., 2015; Lu et al., 2015; Voloshanenko et al., 2013)。WLS 對於分泌所有 Wnt 蛋白很重要。它調節 β-連環蛋白和細胞週期蛋白 D1 的表達,從而影響細胞增殖 (Yang et al., 2015b; Banziger et al., 2006)。WLS (also known as EVI or GPR177) encodes a Wntless Wnt ligand secretion-mediating factor. WLS represents an ancient partner of Wnt dedicated to promoting its secretion into the extracellular milieu (Banziger et al., 2006). WLS is overexpressed in different cancer entities, including breast, gastric, ovarian and colorectal cancer, and leukemia, and is associated with poor prognosis (Chiou et al., 2014; Stewart et al., 2015; Lu et al., 2015; Voloshanenko et al., 2013). WLS is important for the secretion of all Wnt proteins. It regulates the expression of β-catenin and cyclin D1, thereby affecting cell proliferation (Yang et al., 2015b; Banziger et al., 2006).
YIF1A 編碼 Yip1 相互作用因數同源物 A,位於染色體 11q13上(RefSeq, 2002)。在肝細胞癌的 YIF1A 基因中已檢測到多個突變(擴增和缺失)(Nalesnik et al., 2012)。YIF1A 表達顯示正常和鱗狀細胞癌樣本之間存在顯著差異 (Sugimoto et al., 2009)。YIF1A encodes the Yip1 interaction factor homolog A, located on chromosome 11q13 (RefSeq, 2002). Multiple mutations (amplifications and deletions) have been detected in the YIF1A gene in hepatocellular carcinoma (Nalesnik et al., 2012). YIF1A expression showed significant differences between normal and squamous cell carcinoma samples (Sugimoto et al., 2009).
ZRANB3 編碼鋅指蛋白、含 RAN 結合結構域 3,位於染色體 2q21.3 上 (RefSeq, 2002)。ZRANB3 編碼鋅指蛋白,這是一種結構特異性 ATP 依賴性核酸內切酶。它參與複製應激反應以保持基因組的完整性 (Ciccia et al., 2012; Weston et al., 2012)。單核苷酸多態性 rs4954256,位於染色體 2q21.3 上的 ZRANB3 內,與食管癌治療中的同步放化療病理完全反應 3.93 倍增加有關 (Chen et al., 2012)。ZRANB3 在子宮內膜癌中常突變 (Lawrence et al., 2014)。ZRANB3 encodes a zinc finger protein containing RAN-binding
是否能刺激免疫反應取決於是否存在被宿主免疫系統視為異物的抗原。發現腫瘤相關抗原的存在增加了運用宿主免疫系統干預腫瘤生長的可能性。目前,針對癌症免疫治療,正在探索利用免疫系統的體液和細胞進行免疫的各種機制。The ability to stimulate an immune response depends on the presence of antigens that are considered foreign by the host immune system. The discovery of the presence of tumor-associated antigens raises the possibility of using the host immune system to intervene in tumor growth. Currently, for cancer immunotherapy, various mechanisms that utilize the humors and cells of the immune system for immunity are being explored.
細胞免疫反應的特定元素能特異性地識別和破壞腫瘤細胞。從腫瘤浸潤細胞群或外周血中分離出的 T-細胞表明,這些細胞在癌症的天然免疫防禦中發揮了重要作用。特別是 CD8 陽性 T 細胞在這種反應中發揮重要作用,TCD8 +能識別通常8至10個源自蛋白或位於細胞質的缺損核糖體產物 (DRIP) 的氨基酸殘基的主要組織相容性複合體 (MHC) 所載的肽中所含的I類分子。人 MHC 分子也稱為人白細胞-抗原 (HLA)。 Certain elements of the cellular immune response specifically recognize and destroy tumor cells. T-cells isolated from tumor-infiltrating cell populations or peripheral blood suggest that these cells play an important role in the innate immune defense of cancer. In particular, CD8-positive T cells play an important role in this response, and TCD8 + recognizes major histocompatibility complexes of typically 8 to 10 amino acid residues derived from proteins or from defective ribosomal products (DRIPs) located in the cytoplasm. (MHC) Class I molecules contained in peptides. Human MHC molecules are also known as human leukocyte-antigens (HLA).
術語「T 細胞反應」是指由一種肽在體外或體內誘導的效應子功能的特異性擴散和啟動。對於 MHC I 類限制性細胞毒性 T 細胞,效應子功能可能為溶解肽脈衝的、肽前體脈衝的或天然肽表現的靶細胞、分泌細胞因數,優選為肽誘導的干擾素-γ,TNF-α 或 IL-2,分泌效應分子,優選為肽誘導的顆粒酶或穿孔素,或脫顆粒。The term "T cell response" refers to the specific diffusion and initiation of effector functions induced by a peptide in vitro or in vivo. For MHC class I-restricted cytotoxic T cells, effector functions may be lysis of peptide-pulsed, peptide-precursor-pulsed or native peptide-expressed target cells, secretion of cytokines, preferably peptide-induced interferon-γ, TNF- Alpha or IL-2, secreted effector molecules, preferably peptide-induced granzymes or perforin, or degranulation.
本文所用「肽」這一術語,系指一系列氨基酸殘基,通常通過相鄰氨基酸的 α-氨基和羰基之間的肽鍵來連接。這些肽的長度優選為 9 個氨基酸,但至短可為 8 個氨基酸長度,至長可為 10、11、12 或 13 個氨基酸長度或更長,如果為 MHC-II 類肽時(本發明肽的拉長變體),至長可為 14、15、16、17、18 、19 或 20 個氨基酸長度或更長。As used herein, the term "peptide" refers to a series of amino acid residues, usually joined by peptide bonds between the alpha-amino groups and carbonyl groups of adjacent amino acids. These peptides are preferably 9 amino acids in length, but can be as short as 8 amino acids in length, and as long as 10, 11, 12 or 13 amino acids in length or longer, in the case of MHC class II peptides (peptides of the invention). elongated variants), up to 14, 15, 16, 17, 18, 19 or 20 amino acids in length or longer.
因此,「肽」這一術語應包括一系列氨基酸殘基的鹽,通常通過相鄰氨基酸的 α-氨基和羰基之間的肽鍵來連接。優選的情況是,鹽為肽的藥用鹽,例如:氯化物或乙酸(三氟乙酸)鹽。必須注意的是,本發明肽的鹽與其體內狀態的肽基本上不同,因為該不是體內的鹽。Thus, the term "peptide" shall include salts of a series of amino acid residues, usually joined by peptide bonds between the α-amino groups and carbonyl groups of adjacent amino acids. Preferably, the salt is a pharmaceutically acceptable salt of the peptide, such as a chloride or acetic acid (trifluoroacetic acid) salt. It must be noted that the salt of the peptide of the present invention is substantially different from the peptide in its in vivo state, since it is not a salt in vivo.
術語「肽」應也包括「寡肽」。本文使用的術語「寡肽」是指一系列氨基酸殘基,通常通過相鄰氨基酸的 α-氨基和羰基之間的肽鍵來連接。寡肽的長度對於本發明來說並不十分關鍵,只要在寡肽中保持正確的表位即可。通常,寡肽長度約小於 30 個氨基酸殘基,約長於 15 個氨基酸。The term "peptide" shall also include "oligopeptide". The term "oligopeptide" as used herein refers to a series of amino acid residues, usually linked by peptide bonds between the alpha-amino groups and carbonyl groups of adjacent amino acids. The length of the oligopeptide is not critical to the present invention as long as the correct epitope is maintained in the oligopeptide. Typically, oligopeptides are less than about 30 amino acid residues and longer than about 15 amino acids in length.
「多肽」這一術語是指一系列氨基酸殘基,通常通過相鄰氨基酸的 α-氨基和羰基之間的肽鍵來連接。多肽的長度對於本發明來說並不十分關鍵,只要保持正確的表位即可。與術語肽或寡肽相對,「多肽」這一術語是指包含多於約 30 個氨基酸殘基的分子。The term "polypeptide" refers to a series of amino acid residues, usually linked by peptide bonds between the α-amino groups and carbonyl groups of adjacent amino acids. The length of the polypeptide is not critical to the present invention as long as the correct epitope is maintained. In contrast to the terms peptide or oligopeptide, the term "polypeptide" refers to a molecule comprising more than about 30 amino acid residues.
一種肽、寡肽、蛋白質或編碼該分子的核苷酸如果能誘導免疫反應,則具有「免疫原性」(因此是本發明中的一種「免疫原」)。在本發明的情況下,免疫原性的更具體定義是誘導 T 細胞反應的能力。因此,「免疫原」是一種能夠誘導免疫反應的分子,並且在本發明的情況下,是一種能誘導 T 細胞反應的分子。在另一方面,所述免疫原可以是肽,肽與 MHC 的複合體、和/或用於提高特異性抗體或 TCR 抗性的蛋白。A peptide, oligopeptide, protein or nucleotide encoding the molecule is "immunogenic" (hence an "immunogen" in the present invention) if it induces an immune response. In the context of the present invention, a more specific definition of immunogenicity is the ability to induce a T cell response. Thus, an "immunogen" is a molecule capable of inducing an immune response, and in the context of the present invention, a molecule capable of inducing a T cell response. In another aspect, the immunogen can be a peptide, a complex of a peptide with MHC, and/or a protein used to increase specific antibody or TCR resistance.
I 類 T 細胞「表位」要求的是一種結合至 MHC I 類受體上的短肽,從而形成一種三元複合體(MHC I 類 α鏈、β-2-微球蛋白和肽),其可以通過 T 細胞負載匹配 T 細胞受體與具有適當親和力的 MHC/肽複合物結合來識別。結合至 MHC I 類分子的肽的典型長度為 8-14 個氨基酸,最典型為 9 個氨基酸長度。A class I T cell "epitope" requires a short peptide that binds to the MHC class I receptor to form a ternary complex (MHC class I alpha chain, beta-2-microglobulin, and peptide) that Recognition can be achieved by T cell load-matched T cell receptor binding to MHC/peptide complexes with appropriate affinity. Peptides that bind to MHC class I molecules are typically 8-14 amino acids in length, most typically 9 amino acids in length.
在人類中,有三種編碼 MHC I 類分子的不同基因位點(人 MHC分子也是指定的人白細胞抗原 (HLA)):HLA-A、HLA-B 和 HLA-C。HLA-A*01、HLA-A*02 和 HLA-B*07 是可從這些基因位點表達的不同 MHC I 類等位元基因的實例。
表 5:HLA-A*02 和 HLA-A*24 和最常見 HLA-DR 血清類型的表達頻率 F。頻率根據 Mori 等人 (Mori et al., 1997) 使用的 Hardy-Weinberg 公式 F = 1 – (1-Gf)² 改編,從美國人群範圍內的單體型頻率中推導出。由於連鎖不平衡,某些 HLA-DR 等位基因內的 A*02 或 A*24 組合與其預期單一頻率相比,可能是濃縮的或頻率較低。有關詳細資訊,請參閱 Chanock 等人的文獻 (Chanock et al., 2004)。
本發明的肽,優選當如本文描述納入本發明的疫苗時與 A*02。疫苗還可能包括泛結合 MHC II 類肽。因此,本發明的疫苗可用於治療 A*02 陽性患者中的癌症,但不因為這些肽的廣泛結核性而必須選擇 II 類 MHC 同種異型。The peptides of the invention, preferably when incorporated into the vaccines of the invention as described herein, are combined with A*02. Vaccines may also include pan-binding MHC class II peptides. Thus, the vaccines of the present invention can be used to treat cancer in A*02 positive patients, but the MHC class II allotypes are not necessitated by the extensive tuberculous nature of these peptides.
如果本發明的 A*02 肽與結合至另一等位基因例如 A*24 的肽組合,與單獨的 MHC I 類等位基因相比,可治療更高比例的患者群體。雖然在大多數人群中,低於 50% 的患者可由單獨的等位基因來解決問題,但是本發明中一種含 HLA-A*24 和 HLA-A*02 表位的疫苗可以治療任何相關人群中至少 60% 的患者。具體來說,各區域中,以下比例的患者這些等位基因中的至少一個有肯定效果:美國 61%、西歐 62%、中國 75%、韓國 77%、日本 86%(根據 www.allelefrequencies.net 計算)。If the A*02 peptide of the invention is combined with a peptide that binds to another allele, such as A*24, a higher proportion of the patient population can be treated than the MHC class I allele alone. Although in most populations less than 50% of patients can be resolved by alleles alone, a vaccine of the present invention containing HLA-A*24 and HLA-
在一項優選的實施方案中,術語「核苷酸序列」系指去氧核苷酸的雜聚物。In a preferred embodiment, the term "nucleotide sequence" refers to a heteropolymer of deoxynucleotides.
編碼特定肽、寡肽或多肽的核苷酸序列可為天然核苷酸序列,也可為合成核苷酸序列。一般來說,編碼肽、多肽以及本發明蛋白的 DNA 片段由 cDNA 片段和短寡核苷酸銜接物,或一系列寡核苷酸組成,以提供一種合成基因,該基因能夠在包含源自微生物或病毒操縱子的調節元素的重組轉錄單元中被表達。The nucleotide sequence encoding a particular peptide, oligopeptide or polypeptide can be a natural nucleotide sequence or a synthetic nucleotide sequence. Generally, DNA fragments encoding peptides, polypeptides, and proteins of the present invention consist of cDNA fragments and short oligonucleotide linkers, or a series of oligonucleotides, to provide a synthetic gene capable of Or the regulatory elements of the viral operon are expressed in recombinant transcription units.
如本文所用的術語「肽的核苷酸編碼」系指對肽進行核苷酸序列編碼,其中該肽包括與將由用於產生 TCR 的樹突細胞或另一細胞系統所表達該序列的生物系統相容的人工(人造)啟動和停止密碼子。The term "nucleotide encoding of a peptide" as used herein refers to the encoding of a nucleotide sequence of a peptide, wherein the peptide includes a biological system in which the sequence is to be expressed by dendritic cells or another cellular system used to produce the TCR. Compatible artificial (artificial) start and stop codons.
本文提到的核酸序列既包括單鏈核酸也包括雙鏈核酸。因此,除非本文另有所指,否則,例如對於 DNA,具體的序列是該序列的單鏈 DNA、該序列與其互補序列的雙工(雙鏈 DNA)以及該序列的互補序列。Nucleic acid sequences referred to herein include both single-stranded and double-stranded nucleic acids. Thus, unless otherwise indicated herein, for example with respect to DNA, a specific sequence is the single-stranded DNA of that sequence, the duplex (double-stranded DNA) of that sequence and its complement, and the complement of that sequence.
「編碼區」這一術語是指在基因的天然基因組環境中天然或正常編碼該基因的表達產物的那部分基因,即,體內編碼該基因的天然表達產物的區域。The term "coding region" refers to that portion of a gene that naturally or normally encodes the expression product of the gene in its native genomic environment, ie, the region that encodes the native expression product of the gene in vivo.
編碼區可來自非突變(「正常」)基因、突變基因或異常基因,甚至還可以來自 DNA 序列,完全可在實驗室中使用本領域熟知的 DNA 合成方法合成。Coding regions can be derived from non-mutated ("normal") genes, mutated or abnormal genes, or even from DNA sequences, and can be synthesized in the laboratory using DNA synthesis methods well known in the art.
「表達產物」這一術語是指多肽或蛋白,它是基因和遺傳碼退化並因而編碼同樣的氨基酸所造成的任何核酸序列編碼同等物的翻譯產物。The term "expression product" refers to a polypeptide or protein that is the translation product of any nucleic acid sequence encoding an equivalent resulting from the degeneration of the gene and genetic code and thus encoding the same amino acid.
「片斷」這一術語,當指的是一種編碼序列時,表示包含非完整編碼區的 DNA 的一部分,其表達產物與完整編碼區表達產物基本上具有相同的生物學功能或活性。The term "fragment", when referring to a coding sequence, refers to a portion of DNA comprising an incomplete coding region whose expression product has substantially the same biological function or activity as the expression product of the complete coding region.
「DNA 片段」這一術語是指一種 DNA 聚合物,以單獨的片段形式或一種較大 DNA 結構的組分形式存在,它們從至少分離過一次的 DNA 中以基本純淨的形式獲得,即不含污染性內源性材料,並且獲得的數量或濃度能夠使用標準生化方法,例如使用克隆載體,進行識別、操縱和回收該片段及其組分核苷酸序列。此類片段以開放閱讀框架(未被內部未翻譯序列打斷)或內含子(通常表現于真核基因中)的形式存在。未翻譯 DNA 序列可能存在於開放閱讀框架的下游,在那裏其不會干預編碼區的操縱或表達。The term "DNA fragment" refers to a DNA polymer, in the form of individual fragments or components of a larger DNA structure, obtained in substantially pure form, i.e. free from DNA that has been isolated at least once Contaminating endogenous material, and the resulting amounts or concentrations enable identification, manipulation and recovery of the fragment and its component nucleotide sequences using standard biochemical methods, such as the use of cloning vectors. Such fragments exist in the form of open reading frames (uninterrupted by internal untranslated sequences) or introns (usually present in eukaryotic genes). Untranslated DNA sequences may exist downstream of the open reading frame, where they do not interfere with the manipulation or expression of the coding region.
「引物」這一術語表示一種短核酸序列,其可與一個 DNA 鏈配對,並在 DNA 聚合酶開始合成去氧核糖核酸鏈之處提供一個游離的 3'-OH 末端。The term "primer" refers to a short nucleic acid sequence that pairs with a DNA strand and provides a free 3'-OH terminus where DNA polymerase begins synthesizing the deoxyribonucleic acid strand.
「啟動子」這一術語表示參與 RNA 聚合酶的結合從而啟動轉錄的 DNA 區域。The term "promoter" refers to the region of DNA involved in the binding of RNA polymerase to initiate transcription.
術語「分離」表示一種物質從其原來的環境(例如,如果是天然發生的則是天然環境)中被移走。例如,活體動物中的天然核苷酸或多肽不是分離的,但是,從天然系統中一些或所有共存物質中分離出來的核苷酸或多肽是分離的。此類多核苷酸可能是載體的一部分和/或此類多核苷酸和多肽可能是一種組合物的一部分,並且由於該載體或組合物不是其天然環境的一部分,因此它仍然是分離的。The term "isolated" means that a substance is removed from its original environment (eg, the natural environment if it occurs in nature). For example, native nucleotides or polypeptides in living animals are not isolated, but nucleotides or polypeptides that are isolated from some or all coexisting species in the native system are isolated. Such polynucleotides may be part of a vector and/or such polynucleotides and polypeptides may be part of a composition, and since the vector or composition is not part of its natural environment, it remains isolated.
本發明中披露的多核苷酸和重組或免疫原性多肽也可能以「純化」的形式存在。術語「純化」並非要求絕對的純度;它只是一個相對的定義,可以包括高度純化或部分純化的製劑,相關領域技術人員能理解這些術語。例如,各個從已用傳統方法純化為具有電泳同質性的 cDNA 庫中分離出的各種克隆物。明確考慮到將起始材料或天然物質純化至少一個數量級,優選為兩或三個數量級,更優選為四或五個數量級。此外,明確涵蓋所述多肽的純度優選為 99.999%,或至少為 99.99% 或 99.9%;甚而適宜為以重量計 99% 或更高。The polynucleotides and recombinant or immunogenic polypeptides disclosed in the present invention may also exist in "purified" form. The term "purified" does not require absolute purity; it is only a relative definition and can include highly purified or partially purified preparations, as those terms are understood by those skilled in the relevant art. For example, each clone is isolated from a cDNA library that has been conventionally purified to electrophoretic homogeneity. It is expressly contemplated to purify the starting material or natural substance by at least one order of magnitude, preferably two or three orders of magnitude, more preferably four or five orders of magnitude. Furthermore, it is expressly contemplated that the polypeptide is preferably 99.999% pure, or at least 99.99% or 99.9% pure; even suitably 99% by weight or higher.
根據本發明公開的核酸和多肽表達產物,以及包含此類核酸和/或多肽的表達載體可能以「濃縮的形式」存在。本文使用的術語「濃縮」是指材料的濃度至少是其自然濃度的大約 2、5、10、100 或 1000 倍,有優勢的是,按重量計為 0.01%,優選為至少 0.1%。也明確考慮到,按重量計約為 0.5%、1%、5%、10% 和 20% 的濃縮製劑。序列、構型、載體、克隆物以及包含本發明的其他材料可有優勢地以濃縮或分離的形式存在。「活性片段」這一術語是指產生免疫反應的片段(即具有免疫原性活性),通常是一種肽、多肽或核酸序列的片段,不論是單獨或可選地與合適的佐劑一起或在載體中給予一種動物,比如哺乳動物,例如兔子或小鼠,也包括人;這種免疫反應採用的形式是在接受動物(如:人)體內刺激 T 細胞反應。或者,「活性片段」也可用於誘導體外 T 細胞反應。Nucleic acid and polypeptide expression products disclosed in accordance with the present invention, as well as expression vectors comprising such nucleic acids and/or polypeptides, may exist in "concentrated form". The term "concentrated" as used herein refers to a concentration of a material that is at least about 2, 5, 10, 100 or 1000 times its natural concentration, advantageously 0.01% by weight, preferably at least 0.1%. Concentrated formulations of about 0.5%, 1%, 5%, 10% and 20% by weight are also expressly contemplated. Sequences, configurations, vectors, clones, and other materials comprising the present invention may advantageously exist in concentrated or isolated form. The term "active fragment" refers to a fragment that produces an immune response (ie, has immunogenic activity), usually a fragment of a peptide, polypeptide or nucleic acid sequence, either alone or optionally with a suitable adjuvant or in the presence of The vehicle is administered to an animal, such as a mammal, such as a rabbit or a mouse, but also to humans; the immune response takes the form of stimulating a T cell response in the recipient animal (eg, a human). Alternatively, "active fragments" can also be used to induce T cell responses in vitro.
本文使用的「部分」(portion)、「節段」(segment)、「片段」(fragment) 這幾個術語,當與多肽相關地使用時是指殘基的連續序列,比如氨基酸殘基,其序列形成一個較大序列的子集。例如,如果一個多肽以任一種肽鏈內切肽酶(如胰蛋白酶或糜蛋白酶)進行處理,則該處理獲得的寡肽會代表起始多肽的部分、節段或片段。當與多核苷酸相關地使用時,這些術語系指用任何核酸內切酶處理所述多核苷酸產生的產物。The terms "portion," "segment," "fragment" as used herein, when used in relation to a polypeptide, refer to a contiguous sequence of residues, such as amino acid residues, which Sequences form a subset of a larger sequence. For example, if a polypeptide is treated with any of the endopeptidase enzymes (eg, trypsin or chymotrypsin), the resulting oligopeptide will represent a portion, segment, or fragment of the starting polypeptide. When used in relation to a polynucleotide, these terms refer to the product resulting from treatment of the polynucleotide with any endonuclease.
根據本發明,術語「等同度百分比」或「等同百分比」,如果指的是序列,則表示在待對比序列(「被對比序列」)與所述序列或請求的序列(「參考序列」)對準之後將被對比序列與所述序列或請求的序列進行比較。然後根據下列公式計算等同度百分比:
等同度百分比= 100 [1 -(C/R)]
其中 C 是參考序列與被對比序列之間對準長度上參考序列與被對比序列之間的差異數量,其中
(i) 參考序列中每個堿基或氨基酸序列在被對比序列中沒有對應的對準堿基或氨基酸;
(ii) 參考序列中每個空隙,以及
(iii) 參考序列中每個對準堿基或氨基酸與被比對比序列中對準堿基或氨基酸不同,即構成一個差異以及
(iiii) 必須在對準序列的第 1 位置開始對準;
並且 R 是參考序列與被對比序列對準長度上在參考序列中產生任何空隙也計算為一個堿基或氨基酸的參考序列中的堿基或氨基酸數目。
According to the present invention, the term "percent equivalence" or "percent equivalence", if referring to a sequence, means that the sequence to be compared (the "aligned sequence") is aligned with the sequence or the requested sequence (the "reference sequence"). The aligned sequences are then compared to the sequence or the requested sequence after alignment. The percent equivalence is then calculated according to the following formula:
Percent Equivalence = 100 [1 -(C/R)]
where C is the number of differences between the reference and compared sequences in the alignment length between the reference and compared sequences, where
(i) each base or amino acid sequence in the reference sequence has no corresponding alignment base or amino acid in the sequence being compared;
(ii) each gap in the reference sequence, and
(iii) each alignment base or amino acid in the reference sequence is different from the alignment base or amino acid in the aligned sequence, i.e. constitutes a difference and
(iii) Alignment must begin at
如果「被對比序列」和「參考序列」之間存在的一個對準按上述計算的等同度百分比大致等於或大於指定的最低等同度百分比,則被對比序列與參考序列具有指定的最低等同度百分比,雖然可能存在按本文上述計算的等同度百分比低於指定等同度百分比的對準。A compared sequence has a specified minimum percent identity to the reference sequence if there is an alignment between the "aligned sequence" and the "reference sequence" whose percent identity calculated above is approximately equal to or greater than the specified minimum percent identity , although there may be alignments where the percent equivalence calculated as described above is lower than the specified percent equivalence.
因此,如上所述,本發明提出了一種肽,其包括選自 SEQ ID NO:1 至 SEQ ID NO:161 群組的一個序列、或與 SEQ ID NO:1 至 SEQ ID NO:161 具有 88% 同源性的其變體、或誘導與該肽發生T細胞交叉反應的一個變體。本發明所述的肽具有與主要組織相容性複合體 (MHC) I 或所述肽拉長版本的 II 類分子結合的能力。Therefore, as described above, the present invention proposes a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 161, or having 88% with SEQ ID NO: 1 to SEQ ID NO: 161 A homologous variant thereof, or a variant that induces T cell cross-reactivity with the peptide. The peptides of the present invention have the ability to bind to major histocompatibility complex (MHC) I or class II molecules of elongated versions of the peptides.
在本發明中,「同源性」一詞系指兩個氨基酸序列之間的同一度(參見上文的等同度百分比,如肽或多肽序列。前文所述的「同源」是通過將理想條件下調整的兩個序列與待比較序列進行比對後確定的。此類序列同源性可通過使用 ClustalW 等演算法創建一個排列而進行計算。也可用使用一般序列分析軟體,更具體地說,是 Vector NTI、GENETYX 或由公共資料庫提供的其他工具。In the present invention, the term "homology" refers to the degree of identity (see above for percent identity) between two amino acid sequences, such as peptide or polypeptide sequences. The two sequences adjusted under the conditions are determined by aligning them with the sequences to be compared. Such sequence homology can be calculated by creating an alignment using algorithms such as ClustalW. It is also possible to use general sequence analysis software, more specifically , is Vector NTI, GENETYX, or other tools provided by public repositories.
本領域技術人員能評估特定肽變體誘導的 T 細胞是否可與該肽本身發生交叉反應 (Appay et al., 2006; Colombetti et al., 2006; Fong et al., 2001; Zaremba et al., 1997)。One skilled in the art can assess whether T cells induced by a particular peptide variant can cross-react with the peptide itself (Appay et al., 2006; Colombetti et al., 2006; Fong et al., 2001; Zaremba et al., 1997).
發明人用給定氨基酸序列的「變體」表示,一個或兩個氨基酸殘基等的側鏈通過被另一個天然氨基酸殘基的側鏈或其他側鏈取代而發生改變,這樣,這種肽仍然能夠以含有給定氨基酸序列(由 SEQ ID NO:1 至 SEQ ID NO:161 組成)的肽大致同樣的方式與 HLA 分子結合。例如,一種肽可能被修飾以便至少維持(如沒有提高)其能與 HLA-A*02 或 -DR 等合適 MHC 分子的結合槽相互作用和結合,以及至少維持(如沒有提高)其與啟動 T 細胞的 TCR 結合的能力。The inventors use "variants" of a given amino acid sequence to mean that the side chain of one or two amino acid residues, etc., is altered by substitution by the side chain of another natural amino acid residue or other side chains, such that the peptide It is still possible to bind to HLA molecules in much the same way as a peptide containing a given amino acid sequence consisting of SEQ ID NO: 1 to SEQ ID NO: 161. For example, a peptide may be modified to at least maintain (if not increase) its ability to interact and bind to the binding groove of a suitable MHC molecule such as HLA-A*02 or -DR, and to at least maintain (if not increase) its ability to interact with the promoter T TCR binding capacity of cells.
隨後,這些 T 細胞可與細胞和殺傷細胞發生交叉反應,這些細胞表達多肽(其中包含本發明中定義的同源肽的天然氨基酸序列)。正如科學文獻和資料庫 (Rammensee et al., 1999; Godkin et al., 1997) 中所述,HLA-A 結合肽的某些位點通常為錨定殘基,可形成一種與 HLA 結合槽的結合模序相稱的核心序列,其定義由構成結合槽的多肽鏈的極性、電物理、疏水性和空間特性確定。因此,本領域技術人員能夠通過保持已知的錨殘基來修飾 SEQ ID No: 1 至 SEQ ID NO:161 提出的氨基酸序列,並且能確定這些變體是否保持與 MHC I 或 II 類分子結合的能力。本發明的變體保持與啟動 T 細胞的 TCR 結合的能力,隨後,這些 T 細胞可與表達一種包含本發明定義的同源肽的天然氨基酸序列的多肽的細胞發生交叉反應並殺死該等細胞。These T cells can then cross-react with cells and killer cells that express polypeptides comprising the native amino acid sequences of homologous peptides as defined in the present invention. As described in the scientific literature and databases (Rammensee et al., 1999; Godkin et al., 1997), certain sites of HLA-A-binding peptides are often anchor residues that form a The binding motif is commensurate with the core sequence, which is defined by the polar, electrophysical, hydrophobic and steric properties of the polypeptide chains that make up the binding groove. Thus, one skilled in the art can modify the amino acid sequences set forth in SEQ ID NO: 1 to SEQ ID NO: 161 by maintaining known anchor residues, and can determine whether these variants retain binding to MHC class I or II molecules ability. The variants of the present invention retain the ability to bind to TCRs that prime T cells, which can then cross-react with and kill cells expressing a polypeptide comprising the native amino acid sequence of a homologous peptide as defined in the present invention .
如果無另有說明,那麼本文公開的原始(未修飾)肽可以通過在肽鏈內的不同(可能為選擇性)位點上取代一個或多個殘基而被修飾。優選情況是,這些取代位於氨基酸鏈的末端。此取代可能是保守性的,例如,其中一個氨基酸被具有類似結構和特點的另一個氨基酸所取代,比如其中一個疏水性氨基酸被另一個疏水性氨基酸取代。更保守的取代是具有相同或類似的大小和化學性質的氨基酸間的取代,例如,亮氨酸被異亮氨酸取代。在天然同源蛋白質家族序列變異的研究中,某些氨基酸的取代往往比其他氨基酸更具有耐受性,這些氨基酸往往表現出與原氨基酸的大小、電荷、極性和疏水性之間的相似性相關,這是確定「保守取代」的基礎。If not stated otherwise, the original (unmodified) peptides disclosed herein may be modified by substituting one or more residues at different (possibly selective) sites within the peptide chain. Preferably, these substitutions are at the ends of the amino acid chain. Such substitutions may be conservative, eg, where one amino acid is replaced by another amino acid of similar structure and characteristics, such as where one hydrophobic amino acid is replaced by another hydrophobic amino acid. More conservative substitutions are those between amino acids of the same or similar size and chemistry, eg, leucine is replaced by isoleucine. In studies of sequence variation in natural homologous protein families, substitutions of certain amino acids tend to be more tolerated than others, and these amino acids often exhibit similarities between the size, charge, polarity, and hydrophobicity of the original amino acid. , which is the basis for determining "conservative substitution".
在本文中,保守取代定義為在以下五種基團之一的內部進行交換:基團 1 — 小脂肪族、非極性或略具極性的殘基 (Ala, Ser, Thr, Pro, Gly);基團 2 — 極性、帶負電荷的殘基及其醯胺 (Asp, Asn, Glu, Gln) ;基團 3 — 極性、帶正電荷的殘基 (His, Arg, Lys) ;基團 4 — 大脂肪族非極性殘基 (Met, Leu, Ile, Val, Cys) 以及基團 5 — 大芳香殘基 (Phe, Tyr, Trp)。In this context, conservative substitution is defined as an exchange within one of the following five groups: group 1 - a small aliphatic, non-polar or slightly polar residue (Ala, Ser, Thr, Pro, Gly); Group 2 - polar, negatively charged residues and their amides (Asp, Asn, Glu, Gln); Group 3 - polar, positively charged residues (His, Arg, Lys); Group 4 - Large aliphatic nonpolar residues (Met, Leu, Ile, Val, Cys) and group 5 - large aromatic residues (Phe, Tyr, Trp).
較不保守的取代可能涉及一個氨基酸被另一個具有類似特點但在大小上有所不同的氨基酸所取代,如:丙氨酸被異亮氨酸殘基取代。高度不保守的取代可能涉及一個酸性氨基酸被另一個具有極性或甚至具有鹼性性質的氨基酸所取代。然而,這種「激進」取代不能認為是無效的而不予考慮,因為化學作用是不完全可預測的,激進的取代可能會帶來其簡單化學原理中無法預見的偶然效果。Less conservative substitutions may involve the replacement of one amino acid by another amino acid with similar characteristics but different in size, eg, alanine is replaced by an isoleucine residue. Highly non-conservative substitutions may involve the replacement of an acidic amino acid by another amino acid with polar or even basic properties. However, such "radical" substitutions cannot be dismissed as ineffective because chemical effects are not completely predictable, and radical substitutions may have contingent effects unforeseeable in their simple chemical principles.
當然,這種取代可能涉及普通 L-氨基酸之外的其他結構。因此,D-氨基酸可能被本發明的抗原肽中常見的 L-氨基酸取代,也仍在本公開的範圍之內。此外,非標準氨基酸(即,除了常見的天然蛋白原氨基酸)也可以用於取代之目的,以生產根據本發明的免疫原和免疫原性多肽。Of course, such substitutions may involve other structures than ordinary L-amino acids. Therefore, D-amino acids may be substituted by L-amino acids commonly found in the antigenic peptides of the present invention, and still remain within the scope of this disclosure. In addition, non-standard amino acids (ie, in addition to common natural proteinogenic amino acids) can also be used for substitution purposes to produce immunogens and immunogenic polypeptides according to the present invention.
如果在一個以上位置上的取代發現導致肽的抗原活性基本上等於或大於以下定義值,則對這些取代的組合進行測試,以確定組合的取代是否產生對肽抗原性的疊加或協同效應。肽內被同時取代的位置最多不能超過 4 個。If substitutions at more than one position are found to result in peptide antigenic activity substantially equal to or greater than the values defined below, combinations of these substitutions are tested to determine whether the combined substitutions produce additive or synergistic effects on peptide antigenicity. No more than 4 positions within a peptide can be substituted at the same time.
基本上由本文所指氨基酸序列組成的一種肽可能有一個或兩個非錨定氨基酸(見下面錨基序相關內容)被交換,而不存在這種情況,即相比於未修飾的肽,與人類主要組織相容性複合體 (MHC) –I 或 II 類分子的能力基本上被改變或受到不利影響。在另一實施方案中,在基本上由本文所述氨基酸序列組成的肽中,一個或兩個氨基酸可與其保守交換夥伴交換(見下文),而不存在這種情況,即相比於未修飾的肽,與人類主要組織相容性複合體 (MHC) –I 或 II 類分子的能力基本上被改變或受到不利影響。A peptide consisting essentially of the amino acid sequence referred to herein may have one or two non-anchor amino acids (see below for anchor motifs) exchanged, but this is not the case, i.e., compared to the unmodified peptide, The ability to interact with human major histocompatibility complex (MHC)-class I or II molecules is substantially altered or adversely affected. In another embodiment, in a peptide consisting essentially of the amino acid sequences described herein, one or two amino acids can be exchanged with its conservative exchange partner (see below), but this is not the case, ie, compared to unmodified The ability of peptides to interact with the human major histocompatibility complex (MHC) – class I or II molecules is substantially altered or adversely affected.
這些基本不與 T 細胞受體互動的氨基酸殘基可通過取代其他幾乎不影響 T 細胞反應並不妨礙與相關 MHC 結合的氨基酸而得到修飾。因此,除了特定限制性條件外,本發明的肽可能為任何包括給定氨基酸序列或部分或其變體的肽(發明人所用的這個術語包括寡肽或多肽)。
表 6 :根據 SEQ ID NO: 7 、 32 、 46 和 76 的肽的優選變體和基序
較長(拉長)的肽也可能適合。MHC I 類表位(通常長度為 8 至 11 個氨基酸)可能由肽從較長的肽或包含實際表位的蛋白中加工而產生。兩側有實際表位的殘基優選為在加工過程中幾乎不影響暴露實際表位所需蛋白裂解的殘基。Longer (elongated) peptides may also be suitable. MHC class I epitopes (usually 8 to 11 amino acids in length) may result from peptide processing from longer peptides or proteins containing the actual epitope. Residues flanked by the actual epitope are preferably residues that, during processing, have little effect on the proteolytic cleavage required to expose the actual epitope.
本發明的肽可被拉長多達四個氨基酸,即 1、2、3 或 4 個氨基酸,可按照 4:0 與 0:4之間的任何組合添加至任意一端。本發明的拉長組合可見表 7 。
表 7 : 本發明肽的拉長組合
拉伸/延長的氨基酸可以是所述蛋白或任何其他氨基酸的原序列肽。拉長可用于增強所述肽的穩定性或溶解性。The stretched/extended amino acid can be the prosequence of the protein or any other amino acid. Elongation can be used to enhance the stability or solubility of the peptide.
因此,本發明所述的表位可能與天然腫瘤相關表位或腫瘤特異性表位相同,也可能包括來自參考肽的不超過四個殘基的不同肽,只要它們有基本相同的抗原活性即可。Thus, the epitopes described in the present invention may be identical to native tumor-associated epitopes or tumor-specific epitopes, or may include different peptides of no more than four residues from the reference peptide, as long as they have substantially the same antigenic activity, i.e. Can.
在一項替代實施方案中,肽的一邊或雙邊被拉長 4 個以上的氨基酸,優選最多 30 個氨基酸的總長度。這可形成 MHC-II 類結合肽。結合至 MHC II 類肽可通過本領域中已知的方法進行測試。In an alternative embodiment, one or both sides of the peptide are elongated by more than 4 amino acids, preferably up to a total length of 30 amino acids. This results in the formation of MHC-class II-binding peptides. Binding to MHC class II peptides can be tested by methods known in the art.
因此,本發明提出了 MHC I 類表位的肽和變體,其中所述肽或抗體的總長度為 8 至 100 個、優選為 8 至 30 個、最優選為 8 至 14 個氨基酸長度(即 10、11、12、13、14 個氨基酸,如果為拉長 II 類結合肽時,長度也可為 15、16、17、18 、19 、20、21 或 22 個氨基酸)。Accordingly, the present invention proposes peptides and variants of MHC class I epitopes, wherein the total length of the peptide or antibody is 8 to 100, preferably 8 to 30, most preferably 8 to 14 amino acids in length (i.e. 10, 11, 12, 13, 14 amino acids, or 15, 16, 17, 18, 19, 20, 21 or 22 amino acids in length in the case of an elongated class II binding peptide).
當然,本發明的肽或變體能與人主要組織相容性複合體 (MHC) I 或 II 類分子結合。肽或變體與 MHC 複合物的結合可用本領域內的已知方法進行測試。Of course, the peptides or variants of the invention can bind to human major histocompatibility complex (MHC) class I or II molecules. Binding of peptides or variants to MHC complexes can be tested using methods known in the art.
優選情況是,當本發明的肽特異性 T 細胞相比於取代肽受到檢測時,如果取代肽在相對於背景肽溶解度增加達到最大值的一半,則該肽濃度不超過約 1 mM,優選為不超過約 1 µM,更優選為不超過約 1 nM,再優選為不超過約 100 pM,最優選為不超過約 10 pM。也優選為,取代肽被 一個以上的 T 細胞識別,最少為 2 個,更優選為 3 個。Preferably, when the peptide-specific T cells of the invention are tested relative to the substituted peptide, if the substituted peptide achieves a half-maximal increase in solubility relative to the background peptide, the peptide concentration does not exceed about 1 mM, preferably 1 mM. No more than about 1 µM, more preferably no more than about 1 nM, still more preferably no more than about 100 pM, and most preferably no more than about 10 pM. It is also preferred that the substituted peptide is recognized by more than one T cell, at least two, and more preferably three.
在本發明的一個特別優選實施方案中,肽系由或基本系由根據 SEQ ID NO: 1 至 SEQ ID NO: 161 所選的氨基酸序列組成。In a particularly preferred embodiment of the present invention, the peptide consists or consists essentially of the amino acid sequence selected according to SEQ ID NO: 1 to SEQ ID NO: 161.
基本由「...組成」系指本發明的肽,除了根據 SEQ ID NO: 1 至 SEQ ID NO: 161 中的任一序列或其變體組成外,還含有位於其他 N 和/或 C 端延伸處的氨基酸,而它們不一定能形成作為 MHC 分子表位的肽。Consisting essentially of "consisting of" means a peptide of the invention which, in addition to being composed according to any one of SEQ ID NO: 1 to SEQ ID NO: 161 or a variant thereof, also contains other N- and/or C-terminal Extensions of amino acids that do not necessarily form peptides that act as epitopes on MHC molecules.
但這些延伸區域對有效將本發明中的肽引進細胞具有重要作用。在本發明的一實施例中,該肽為融合蛋白的一部分,含來自 NCBI、GenBank 登錄號 X00497 的 HLA-DR 抗原相關不變鏈(p33,以下稱為「Ii」)的 80 個 N-端氨基酸等。在其他的融合中,本發明的肽可以被融合到本文所述的抗體、或其功能性部分,特別是融合入抗體的序列,以便所述抗體進行特異性靶向作用,或者,例如進入本文所述的樹突狀細胞特異性抗體。However, these extended regions are important for the efficient introduction of the peptides of the present invention into cells. In one embodiment of the present invention, the peptide is part of a fusion protein containing 80 N-termini of the HLA-DR antigen-associated invariant chain (p33, hereinafter referred to as "Ii") from NCBI, GenBank Accession No. X00497 amino acids, etc. In other fusions, the peptides of the invention may be fused to an antibody described herein, or a functional portion thereof, particularly a sequence of the antibody, for specific targeting of the antibody, or, for example, into the text The dendritic cell-specific antibody.
此外,該肽或變體可進一步修飾以提高穩定性和/或與 MHC 分子結合,從而引發更強的免疫反應。肽序列的該類優化方法是本領域內所熟知的,包括,例如,反式肽鍵和非肽鍵的引入。In addition, the peptide or variant can be further modified to increase stability and/or bind to MHC molecules, thereby eliciting a stronger immune response. Such optimization methods for peptide sequences are well known in the art and include, for example, the introduction of trans-peptide bonds and non-peptide bonds.
在反式肽鍵氨基酸中,肽 (-CO-NH -) 並未連接其殘基,但是其肽鍵是反向的。這種逆向反向模擬肽 (retro-inverso peptidomimetics) 可通過本領域已知的方法製備,例如:Meziere 等人在 (Meziere et al., 1997) 中所述的方法,以引用的方式併入本文。這種方法涉及製備包含骨架(而並非側鏈)改變的模擬肽。Meziere 等人 (Meziere et al., 1997) 的研究顯示,這些類比肽有利於 MHC 的結合和輔助性 T 細胞的反應。以 NH-CO 鍵替代 CO-NH 肽鍵的逆向反向肽大大地提高了抗水解性能。In trans-peptide bond amino acids, the peptide (-CO-NH-) has no residues attached to it, but its peptide bond is reversed. Such retro-inverso peptidomimetics can be prepared by methods known in the art, such as those described by Meziere et al. (Meziere et al., 1997), incorporated herein by reference . This method involves the preparation of peptidomimetics that contain backbone (rather than side chain) alterations. A study by Meziere et al. (Meziere et al., 1997) showed that these analogous peptides facilitated MHC binding and helper T cell responses. Retro-inverse peptides with NH-CO bonds instead of CO-NH peptide bonds greatly improved hydrolysis resistance.
非肽鍵為-CH 2-NH、-CH 2S-、-CH 2CH 2-、-CH=CH-、-COCH 2-、-CH(OH)CH 2-和 -CH 2SO-等。美國 4897445 號專利提出了多肽鏈中非肽鍵 (-CH 2-NH) 的非固相合成法,該方法涉及按標準程序合成的多肽以及通過氨基醛和一種含 NaCNBH 3的氨基酸相互作用而合成的非肽鍵。 Non-peptide bonds are -CH2 - NH, -CH2S- , -CH2CH2- , -CH= CH- , -COCH2- , -CH(OH)CH2- and -CH2SO- , among others. US Patent No. 4,897,445 proposes non-solid-phase synthesis of non-peptide bonds ( -CH2 -NH) in polypeptide chains involving polypeptides synthesized according to standard procedures and synthesized by the interaction of aminoaldehydes with an amino acid containing NaCNBH3 of non-peptide bonds.
含上述序列的肽可與其氨基和/或羧基末端的其他化學基團進行合成,從而提高肽的穩定性、生物利用度、和/或親和力等。例如,苄氧羰基、丹醯基等疏水基團或叔丁氧羰基團可加入肽的氨基末端。同樣,乙醯基或 9-芴甲氧羰基可能位於肽的氨基末端。此外,疏水基團、叔丁氧羰基團或氨基團都可能被加入肽的羧基末端。Peptides containing the above sequences can be synthesized with other chemical groups at their amino and/or carboxyl termini, thereby improving the stability, bioavailability, and/or affinity of the peptides. For example, hydrophobic groups such as benzyloxycarbonyl, danyl, or a t-butoxycarbonyl group can be added to the amino terminus of the peptide. Likewise, the acetyl or 9-fluorenylmethoxycarbonyl group may be located at the amino terminus of the peptide. In addition, hydrophobic groups, t-butoxycarbonyl groups or amino groups may all be added to the carboxy terminus of the peptide.
另外,本發明中的所有肽都可能經合成而改變其空間構型。例如,可能使用這些肽的一個或多個氨基酸殘基的右旋體,通常不是其左旋體。更進一步地,本發明中肽的至少一個氨基酸殘基可被熟知的一個非天然氨基酸殘基取代。諸如此類的改變可能有助於增加本發明肽的穩定性、生物利用度和/或結合作用。In addition, all peptides of the present invention may be synthesized to alter their steric configuration. For example, it is possible to use the dextromer of one or more amino acid residues of these peptides, usually not the levorotid. Furthermore, at least one amino acid residue of the peptides of the present invention may be substituted with a well-known unnatural amino acid residue. Changes such as these may help to increase the stability, bioavailability and/or binding of the peptides of the invention.
同樣,本發明中的肽或變體可在合成肽之前或之後通過特異氨基酸的反應而進行化學修飾。此類修飾的實施例為本領域所熟知,例如,在 R. Lundblad 所著的《 Chemical Reagents for Protein Modification》 (3rd ed. CRC Press, 2004) (Lundblad, 2004) 中有概述,以參考文獻的方式併入本文。雖然氨基酸的化學修飾方法無限制,但其包括(但不限於)通過以下方法修飾:醯基化、脒基化、賴氨酸吡哆基化、還原烷基化、以 2,4,6-三硝基苯磺酸 (TNBS) 三硝基苯基化氨基團、通過將半胱氨酸過甲酸氧化為磺基丙氨酸而對羧基團和巰基進行氨基修飾、形成易變衍生物、與其他巰基化合物形成混合二硫化合物、與馬來醯亞胺反應,與碘乙酸或碘乙醯胺羧甲基化、在鹼性 pH 值下與氰酸鹽甲氨醯化。在這方面,技術人員參考了《Current Protocols In Protein Science》 (Eds. Coligan et al. (John Wiley and Sons NY 1995-2000) ) (Coligan et al., 1995) 中第 15 章所述的在蛋白質化學修飾相關的廣泛方法。Likewise, the peptides or variants of the present invention may be chemically modified by the reaction of specific amino acids before or after synthesis of the peptide. Examples of such modifications are well known in the art and are outlined, for example, in "Chemical Reagents for Protein Modification" by R. Lundblad (3rd ed. CRC Press, 2004) (Lundblad, 2004), with reference to method is incorporated herein. While the method of chemical modification of amino acids is not limited, it includes (but is not limited to) modification by the following methods: acylation, amidinoylation, lysine pyridoxylation, reductive alkylation, 2,4,6- Trinitrobenzenesulfonic acid (TNBS) trinitrophenylated amino group, amino modification of carboxyl and sulfhydryl groups by oxidation of cysteine performic acid to sulfoalanine, formation of labile derivatives, and Other sulfhydryl compounds form mixed disulfide compounds, react with maleimide, carboxymethylation with iodoacetic acid or iodoacetamide, and methylated with cyanate at alkaline pH. In this regard, the skilled artisan refers to chapter 15 of Current Protocols In Protein Science (Eds. Coligan et al. (John Wiley and Sons NY 1995-2000)) (Coligan et al., 1995) A wide range of methods related to chemical modification.
簡言之,修飾蛋白質的精氨醯殘基等往往基於於鄰二羰基化合物(如苯甲醯甲醛、2,3 –丁二酮以及 1,2-烯巳二酮)的反應而形成加合物。另一個實施例是丙酮醛與精氨酸殘基的反應。半胱氨酸可在賴氨酸和組氨酸等親核位點不作隨同修飾的情況下就得到修飾。因此,有大量試劑可進行半胱氨酸的修飾。Sigma-Aldrich (http://www.sigma-aldrich.com) 等公司的網站含有具體試劑的資訊。Briefly, arginine residues, etc. that modify proteins are often based on the reaction of ortho-dicarbonyl compounds such as benzaldehyde, 2,3-butanedione, and 1,2-ene diketone to form adducts. thing. Another example is the reaction of glyoxal with arginine residues. Cysteine can be modified without concomitant modification of nucleophilic sites such as lysine and histidine. Therefore, a large number of reagents are available for cysteine modification. Websites of companies such as Sigma-Aldrich (http://www.sigma-aldrich.com) contain information on specific reagents.
蛋白質中二硫鍵的選擇性還原也很普遍。二硫鍵可在生物制藥熱處理中形成和氧化。伍德沃德氏試劑 K 可用於修飾特定的谷氨酸殘基。N-(3-二甲氨基丙基)-N´-乙基-碳二亞胺可用于形成賴氨酸殘基和谷氨酸殘基的分子內交聯。例如:焦碳酸二乙酯是修飾蛋白質組氨酸殘基的試劑。組氨酸也可使用 4-羥基-2-壬烯醛進行修飾。賴氨酸殘基與其他α-氨基團的反應,例如,有利於肽結合到蛋白/肽的表面或交聯處。賴氨酸聚是多(乙烯)乙二醇的附著點,也是蛋白質糖基化的主要修飾位點。蛋白質的蛋氨酸殘基可通過碘乙醯胺、溴乙胺、氯胺 T 等被修飾。Selective reduction of disulfide bonds in proteins is also common. Disulfide bonds can be formed and oxidized during thermal processing of biopharmaceuticals. Woodward's reagent K can be used to modify specific glutamic acid residues. N-(3-Dimethylaminopropyl)-N´-ethyl-carbodiimide can be used to form intramolecular crosslinks of lysine residues and glutamic acid residues. For example: Diethylpyrocarbonate is a reagent for modifying histidine residues in proteins. Histidine can also be modified with 4-hydroxy-2-nonenal. Reaction of lysine residues with other alpha-amino groups, for example, facilitates peptide binding to the surface or cross-linking of proteins/peptides. Lysine poly is the attachment point of poly(ethylene) glycol and the main modification site of protein glycosylation. Methionine residues of proteins can be modified by iodoacetamide, bromoethylamine, chloramine T, etc.
四硝基甲烷和 N-乙醯基咪唑可用於酪氨酸殘基的修飾。經二酪氨酸形成的交聯可通過過氧化氫/銅離子完成。Tetranitromethane and N-acetylimidazole can be used for the modification of tyrosine residues. Crosslinking via dtyrosine can be accomplished by hydrogen peroxide/copper ions.
對色氨酸修飾的最近研究中使用了 N-溴代琥珀醯亞胺、2-羥基-5-硝基苄溴或 3-溴-3-甲基-2- (2 –硝苯巰基) -3H-吲哚 (BPNS-糞臭素)。Recent studies on tryptophan modification have used N-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or 3-bromo-3-methyl-2-(2-nitrophenylthio)- 3H-Indole (BPNS-skatole).
當蛋白與戊二醛、聚乙二醇二丙烯酸酯和甲醛的交聯用於配製水凝膠時,治療性蛋白和含聚乙二醇的肽的成功修飾往往可延長迴圈半衰期。針對免疫治療的變態反應原化學修飾往往通過氰酸鉀的氨基甲醯化實現。Successful modification of therapeutic proteins and polyethylene glycol-containing peptides tends to extend loop half-life when cross-linking of proteins with glutaraldehyde, polyethylene glycol diacrylate, and formaldehyde is used to formulate hydrogels. Chemical modification of allergens for immunotherapy is often achieved by carbamateylation of potassium cyanate.
一種肽或變體,其中肽被修飾或含非肽鍵,優選為本發明的實施例。一般來說,肽和變體(至少含氨基酸殘基之間的肽聯接)可使用 Lukas 等人 (Lukas et al., 1981) 以及此處引用的參考文獻所披露的固相肽合成 Fmoc-聚醯胺模式進行合成。芴甲氧羰基 (Fmoc) 團對 N-氨基提供臨時保護。使用 N, N-二甲基甲醯胺中的 20% 二甲基呱啶中對這種堿高度敏感的保護基團進行重複分裂。由於它們的丁基醚 (在絲氨酸蘇氨酸和酪氨酸的情況下)、丁基酯 (在谷氨酸和天門冬氨酸的情況下)、叔丁氧羰基衍生物 (在賴氨酸和組氨酸的情況下)、三苯甲基衍生物 (在半胱氨酸的情況下) 及 4-甲氧基-2,3,6-三甲基苯磺醯基衍生物 (在精氨酸的情況下),側鏈功能可能會受到保護。只要穀氨醯胺和天冬醯胺為 C-末端殘基,側鏈氨基功能保護所使用的是由 4,4'-二甲氧基二苯基團。固相支撐基於聚二甲基丙烯醯胺聚合物,其由三個單體二甲基丙烯醯胺(骨架單體)、雙丙烯醯乙烯二胺(交聯劑)和 N-丙烯醯肌胺酸甲酯(功能劑)構成。使用的肽-樹脂聯劑為酸敏感的 4 -羥甲基苯氧乙酸衍生物。所有的氨基酸衍生物均作為其預製對稱酸酐衍生物加入,但是天冬醯胺和穀氨醯胺除外,它們使用被逆轉的 N, N-二環己基碳二亞胺/1-羥基苯並三唑介導的耦合程序而加入。所有的耦合和脫保護反應用茚三酮、硝基苯磺酸或 isotin 測試程序監測。合成完成後,用濃度為 95% 含 50% 清道夫混合物的三氟醋酸,從伴隨去除側鏈保護基團的樹脂支承物中裂解肽。常用的清道夫混合物包括乙二硫醇、苯酚、苯甲醚和水,準確的選擇依據合成肽的氨基酸組成。此外,固相和液相方法結合使用對肽進行合成是可能的(例如,請參閱 (Bruckdorfer et al., 2004) 以及本文引用的參考文獻)A peptide or variant, wherein the peptide is modified or contains non-peptide bonds, is preferably an embodiment of the present invention. In general, peptides and variants (containing at least peptide linkages between amino acid residues) can be synthesized using solid-phase peptide synthesis of Fmoc-polymers as disclosed in Lukas et al. (Lukas et al., 1981) and references cited herein. The synthesis was carried out in the amide mode. The fluorenemethoxycarbonyl (Fmoc) group provides temporary protection of the N-amino group. Repeated cleavage of this highly sensitive protecting group in N,N-dimethylformamide was performed using 20% dimethylpyridine in N,N-dimethylformamide. Due to their butyl ethers (in the case of serine threonine and tyrosine), butyl esters (in the case of glutamic acid and aspartic acid), tert-butoxycarbonyl derivatives (in the case of lysine and histidine), trityl derivatives (in the case of cysteine) and 4-methoxy-2,3,6-trimethylbenzenesulfonyl derivatives (in the case of refined amino acid), the side chain function may be protected. As long as glutamine and aspartamine are C-terminal residues, the side chain amino function protection used is by a 4,4'-dimethoxydiphenyl group. The solid phase support is based on a polydimethylacrylamide polymer consisting of three monomers, dimethylacrylamide (backbone monomer), bisacrylethylenediamine (crosslinker) and N-acrylonosamine Methyl acid (functional agent) composition. The peptide-resin linker used was an acid-sensitive 4-hydroxymethylphenoxyacetic acid derivative. All amino acid derivatives were added as their preformed symmetrical anhydride derivatives, except asparagine and glutamine, which used reversed N,N-dicyclohexylcarbodiimide/1-hydroxybenzotrimine azole-mediated coupling procedure was added. All coupling and deprotection reactions were monitored with ninhydrin, nitrobenzenesulfonic acid, or isotin test procedures. After synthesis, the peptide was cleaved from the resin support with removal of side chain protecting groups using 95% trifluoroacetic acid with a 50% scavenger mixture. Commonly used scavenger mixtures include ethanedithiol, phenol, anisole, and water, and the exact selection depends on the amino acid composition of the synthetic peptide. In addition, it is possible to synthesize peptides using a combination of solid-phase and liquid-phase methods (for example, see (Bruckdorfer et al., 2004) and references cited herein)
三氟乙酸用真空中蒸發、隨後用承載粗肽的二乙基乙醚滴定進行去除。用簡單萃取程序(水相凍乾後,該程序制得不含清道夫混合物的肽)清除任何存在的清道夫混合物。肽合成試劑一般可從 Calbiochem-Novabiochem(英國諾丁漢)獲得。Trifluoroacetic acid was removed by evaporation in vacuo followed by titration with diethyl ether bearing the crude peptide. Any scavenger mixture present was removed using a simple extraction procedure (which yielded peptides free of scavenger mixture after aqueous lyophilization). Peptide synthesis reagents are generally available from Calbiochem-Novabiochem (Nottingham, UK).
純化可通過以下技術的任何一種或組合方法進行,如:再結晶法、體積排阻色譜法、離子交換色譜法、疏水作用色譜法以及(通常)反相高效液相色譜法(如使用乙腈/水梯度分離)。Purification can be carried out by any one or a combination of the following techniques, such as: recrystallization, size exclusion chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and (usually) reversed-phase high performance liquid chromatography (eg, using acetonitrile/ water gradient separation).
可以使用薄層色譜法、電泳特別是毛細管電泳、固相萃取(CSPE)、反相高效液相色譜法、酸解後的氨基酸分析、快原子轟擊(FAB)質譜分析以及MALDI和ESI-Q-TOF質譜分析進行肽分析。Thin layer chromatography, electrophoresis especially capillary electrophoresis, solid phase extraction (CSPE), reversed-phase high performance liquid chromatography, amino acid analysis after acid hydrolysis, fast atom bombardment (FAB) mass spectrometry and MALDI and ESI-Q- Peptide analysis was performed by TOF mass spectrometry.
為了選擇過度表現的肽,計算了表現圖,其顯示樣本中位元表現量以及複製變化。該特點使相關腫瘤實體的樣本與正常組織樣本的基線值並列。可通過計算調節線性混合效應模型 (Pinheiro et al., 2015) 的 p 值將以上每個特點併入過度表現分數中,從而通過假髮現率 (Benjamini and Hochberg, 1995) 調整多項檢驗。To select overrepresented peptides, a performance map was calculated showing the amount of median expression across samples as well as replicate variation. This feature juxtaposes samples of relevant tumor entities with baseline values for normal tissue samples. Multiple tests can be adjusted for the false discovery rate (Benjamini and Hochberg, 1995) by incorporating each of these characteristics into the overperformance score by calculating a p-value adjusted for a linear mixed-effects model (Pinheiro et al., 2015).
對於通過質譜法對 HLA 配體的識別和相對定量,對來自衝擊冷凍組織樣本的 HLA 分子進行純化並對 HLA 相關肽進行分離。分離的肽分開,並通過線上納米-電噴霧-電離 (nanoESI) 液相色譜- 譜 (LC-MS) 實驗進行鑒定。由此產生的肽序列的驗證方法是,將胰腺癌樣本(N = 20 個 A*02 陽性樣本)中記錄的 TUMAP 的片段模式與相同序列相應合成參考肽的片段模式進行比較。由於這些肽被直接鑒定為腫瘤細胞 HLA 分子的配體,因此這些結果為胰腺癌上確定肽的加工和表現提供了直接證據。For identification and relative quantification of HLA ligands by mass spectrometry, HLA molecules from shock-frozen tissue samples were purified and HLA-associated peptides isolated. The isolated peptides were separated and identified by in-line nano-electrospray-ionization (nanoESI) liquid chromatography-spectroscopy (LC-MS) experiments. The resulting peptide sequences were validated by comparing the fragment patterns of TUMAPs recorded in pancreatic cancer samples (N = 20 A*02 positive samples) with those of the corresponding synthetic reference peptides of the same sequence. Since these peptides were directly identified as ligands for tumor cell HLA molecules, these results provide direct evidence for the processing and expression of defined peptides on pancreatic cancer.
發現管道 XPRESIDENT® v2.1(例如,參見 US 2013-0096016,並在此通過引用將其整體併入本文)考慮到識別和選擇相關過量表現的候選肽疫苗,這基於與幾種不同的非癌組織和器官相比癌症或其他受感染組織的 HLA 限制肽水準直接相對定量結果。這通過以下方法實現:使用專有資料分析管道處理的 LC-MS 採集資料、結合序列識別演算法、譜聚類、計算離子、保留時間調整、充電狀態卷積以及正態化而開發無標記差異化定量方法。The discovery pipeline XPRESIDENT® v2.1 (see, eg, US 2013-0096016, which is hereby incorporated by reference in its entirety) allows for the identification and selection of relevant overexpressed candidate peptide vaccines based on Direct relative quantification of HLA-restricted peptide levels in tissues and organs compared to cancer or other infected tissues. This is achieved by: LC-MS acquisition of data processed using a proprietary data analysis pipeline, development of label-free differences in conjunction with sequence identification algorithms, spectral clustering, counting ions, retention time adjustment, charge state convolution, and normalization Quantitative methods.
為每種肽和樣本確立了表現水準,包括誤差估計值。腫瘤組織大量表現的肽以及腫瘤與非腫瘤組織和器官中過量表現的肽已經得到確定。Performance levels, including error estimates, were established for each peptide and sample. Peptides that are abundantly expressed in tumor tissue and overexpressed in tumor and non-tumor tissues and organs have been identified.
對來自胰腺癌樣本的 HLA 肽複合物進行純化,並且對 HLA 相關肽使用 LC-MS 進行分離和分析(見實施例)。本申請中包含的所有 TUMAP 使用胰腺癌樣本的方法進行鑒定,確認其在胰腺癌上的表現。HLA-peptide complexes from pancreatic cancer samples were purified, and HLA-related peptides were separated and analyzed using LC-MS (see Examples). All TUMAPs included in this application were identified using methods from pancreatic cancer samples to confirm their performance on pancreatic cancer.
在多個胰腺癌和正常組織上確定的 TUMAP 用無標記 LC-MS 資料的離子計數方法進行量化。該方法假定肽的 LC-MS 信號區域與樣本中其豐度相關。各種 LC-MS 實驗中肽的所有量化信號在集中趨勢基礎上進行正常化,根據每個樣品進行平均,併合併入柱狀圖(被稱為表現圖)。表現圖整合了不同分析方法,如:蛋白資料庫檢索、譜聚類、充電狀態卷積(除電)和保留時間校準和正態化。TUMAPs identified on multiple pancreatic cancer and normal tissues were quantified using ion counting methods from label-free LC-MS data. This method assumes that the LC-MS signal region of a peptide correlates with its abundance in the sample. All quantified signals for peptides in various LC-MS experiments were normalized on a central tendency basis, averaged for each sample, and combined into a histogram (referred to as a performance plot). The performance map integrates different analysis methods such as: protein database search, spectral clustering, charge state convolution (removal of charge) and retention time calibration and normalization.
本發明提出了有利於治療癌腫/腫瘤,優選為治療過量表現或只表現本發明肽的胰腺癌。這些肽由質譜分析法直接顯示出,而由 HLA 分子自然表現于人胰腺癌樣本中。The present invention proposes to facilitate the treatment of cancers/tumors, preferably pancreatic cancers that express excessively or exclusively the peptides of the invention. These peptides were directly revealed by mass spectrometry and naturally expressed by HLA molecules in human pancreatic cancer samples.
與正常組織相比,癌症中高度過量表達肽來源的許多源基因/蛋白質(也指定為「全長蛋白」或「潛在蛋白」)- 本發明相關的「正常組織」是來自大腸(結腸或直腸)健康胰腺細胞或其他正常組織細胞,這表明腫瘤與這些源基因的高度關聯性(見實施例 2)。此外,這些肽本身也在腫瘤組織中過度表現(本發明相關的「腫瘤組織」是指胰腺癌樣本),但不在正常組織中過度表現(見實施例 1)。Many source genes/proteins of peptide origin (also designated as "full-length protein" or "latent protein") are highly overexpressed in cancer compared to normal tissue - "normal tissue" relevant to the present invention is from the large intestine (colon or rectum) Healthy pancreatic cells or other normal tissue cells, which indicate a high tumor association with these source genes (see Example 2). In addition, these peptides themselves are also overexpressed in tumor tissue ("tumor tissue" in the context of the present invention refers to pancreatic cancer samples), but not in normal tissue (see Example 1).
HLA 結合肽能夠被免疫系統識別,特別是 T 淋巴細胞。T 細胞可破壞表現被識別 HLA/肽複合體的細胞(如:表現衍生肽的胰腺癌細胞)。HLA-binding peptides are recognized by the immune system, especially T lymphocytes. T cells can destroy cells expressing recognized HLA/peptide complexes (eg, pancreatic cancer cells expressing derived peptides).
本發明的所有肽已被證明具有刺激 T 細胞反應的能力,並過量表現,因而可用于製備本發明的抗體和/或 TCR,例如可溶性 TCR(參見實施例 3 和實施例 4)。此外,肽與相應的 MHC 組合時,也可用于製備本發明的抗體和/或 TCR,特別是 sTCR。各個方法均為技術人員所熟知,並在各個文獻中可找到。因此,本發明的肽可用于在患者中產生免疫反應,從而能夠毀滅腫瘤細胞。患者的免疫反應能夠通過直接給予患者所述肽或前體物質(如,加長肽、蛋白或編碼這些肽的核酸),較理想是與加強免疫原性的製劑相結合,而進行誘導。源自該治療性疫苗的免疫反應預期能夠高度特異性地對抗腫瘤細胞,因為本發明的目標肽在正常組織上表現的複製數目較少,防止患者發生對抗正常細胞的不良自體免疫反應的風險。All peptides of the present invention have been shown to have the ability to stimulate T cell responses and are overexpressed and thus useful in the preparation of antibodies and/or TCRs of the present invention, such as soluble TCRs (see Examples 3 and 4). In addition, peptides can also be used to prepare antibodies and/or TCRs of the invention, especially sTCRs, when combined with the corresponding MHCs. Various methods are well known to the skilled person and can be found in various literatures. Thus, the peptides of the present invention can be used to generate an immune response in a patient, thereby enabling the destruction of tumor cells. The patient's immune response can be induced by direct administration to the patient of the peptides or precursors (eg, elongated peptides, proteins, or nucleic acids encoding these peptides), ideally in combination with an agent that enhances immunogenicity. Immune responses derived from this therapeutic vaccine are expected to be highly specific against tumor cells, as the target peptides of the present invention are expressed in low replication numbers on normal tissues, preventing the risk of adverse autoimmune responses in patients against normal cells .
本說明書還涉及包含一個 α 鏈和一個 β 鏈 (「α/β TCR」) 的 T 細胞受體 (TCR)。還提供了由 MHC 分子表現時可與 TCR 和抗體結合的 HAVCR1-001 肽。本說明書還涉及核酸、載體和用於表達 TCR 的宿主細胞和本說明書的肽;以及使用它們的方法。This specification also refers to T cell receptors (TCRs) comprising one alpha chain and one beta chain ("alpha/beta TCR"). Also provided are HAVCR1-001 peptides that bind to TCRs and antibodies when expressed by MHC molecules. The present specification also relates to nucleic acids, vectors, and host cells for expressing TCRs and the peptides of the present specification; and methods of using them.
術語「T細胞受體」(縮寫 TCR)是指一種異二聚體分子,其包含一個 α 多肽鏈(α 鏈)和一個 β 多肽鏈(β鏈),其中所述異二聚體受體能夠結合由 HLA 分子表現的肽抗原。該術語還包括所謂的 γ/δ TCR。The term "T cell receptor" (abbreviated TCR) refers to a heterodimeric molecule comprising one alpha polypeptide chain (alpha chain) and one beta polypeptide chain (beta chain), wherein the heterodimeric receptor is capable of Binds to peptide antigens expressed by HLA molecules. The term also includes so-called γ/δ TCRs.
在一個實施方案中,本說明書提供了如本文中所描述的產生 TCR 的方法,該方法包括在適於促進 TCR 表達的條件下培養能夠表達TCR的宿主細胞。In one embodiment, the present specification provides a method of producing a TCR as described herein, the method comprising culturing a host cell capable of expressing a TCR under conditions suitable for promoting expression of the TCR.
另一個方面,本說明書涉及一種根據本說明書的方法,其中所述抗原透過與足夠量的含抗原提成細胞的抗原結合被載入表達於合適抗原表現細胞或人工抗原呈遞細胞表面的 I 或 II 類 MHC 分子,或該抗原透過四聚化被載入 I 或 II 類 MHC 四聚體/ I 或 II 類 MHC 複合單體。In another aspect, the present specification relates to a method according to the present specification, wherein the antigen is loaded into class I or II expressed on the surface of a suitable antigen-expressing cell or artificial antigen-presenting cell by binding to a sufficient amount of antigen containing antigen-presenting cells The MHC molecule, or the antigen is loaded into the MHC class I or II tetramer/MHC class I or II complex monomer by tetramerization.
α/β TCR 的 α 和 β 鏈和 γ/δ TCR 的 γ 和 δ 鏈通常被視為各自有兩個「結構域」,即可變和恒定結構域。可變結構域由可變區 (V) 和連接區 (J) 的組合。可變結構域還可能包括一個前導區 (L)。β 和δ鏈還可能包括一個多樣區 (D)。α 和 β 恒定結構域還可能包括錨定 α 和 β 鏈至細胞膜的 C 末端跨膜 (TM) 結構域。The alpha and beta chains of the alpha/beta TCR and the gamma and delta chains of the gamma/delta TCR are generally considered to have two "domains" each, the variable and constant domains. A variable domain consists of a combination of variable regions (V) and linking regions (J). Variable domains may also include a leader (L). The beta and delta chains may also include a diversity region (D). Alpha and beta constant domains may also include C-terminal transmembrane (TM) domains that anchor the alpha and beta chains to the cell membrane.
相對於γ/δ的TCR,如本文所用的術語 「TCR γ可變域」是指無前導區 (L) 的 TCR γ V (TRGV) 區與 TCR γ (TRGJ) 區的組合,術語 TCR γ恒定結構域是指細胞外TRGC區域,或 C-末端截短 TRGC 序列。同樣地,「TCR δ可變域」是指無前導區 (L) 的 TCR δ V (TRDV) 區與 TCR δ D/J (TRDD/TRDJ) 區的組合,術語 「TCR δ恒定結構域」是指細胞外TRDC區域,或 C-末端截短 TRDC 序列。The term "TCR gamma variable domain" as used herein refers to the combination of a TCR gamma V (TRGV) region without a leader (L) and a TCR gamma (TRGJ) region, relative to a gamma/delta TCR, the term TCR gamma constant Domain refers to the extracellular TRGC region, or C-terminally truncated TRGC sequence. Likewise, a "TCR delta variable domain" refers to the combination of a TCR delta V (TRDV) region without a leader (L) and a TCR delta D/J (TRDD/TRDJ) region, and the term "TCR delta constant domain" is Refers to the extracellular TRDC region, or C-terminally truncated TRDC sequence.
本說明書的 TCR 優選結合至 HAVCR1-001 肽 HLA分子複合體,其具有約 100 µM或更小、約 50 µM或更小、約 25 µM或更小或約 10 µM或更小的結合親和力 (KD)。更為優選的情況是具有約 1 µM或更小、約 100 nM或更小、約 50 nM 或更小或約 25 nM或更小結合親和力的高親和力 TCR。本發明 TCR 優選結合親和力範圍的非限制性示例包括約 1 nM 至約 10 nM;約 10 nM 至約 20 nM;約 20 nM 至約 30 nM;約 30 nM 至約 40 nM;約 40 nM 至約 50 nM;約 50 nM 至約 60 nM;約 60 nM 至約 70 nM;約 70 nM 至約 80 nM;約 80 nM 至約 90 nM;以及約 90 nM 至約 100 nM。The TCR of this specification preferably binds to a HAVCR1-001 peptide HLA molecule complex having a binding affinity (KD of about 100 µM or less, about 50 µM or less, about 25 µM or less, or about 10 µM or less ). More preferred are high affinity TCRs with binding affinity of about 1 μM or less, about 100 nM or less, about 50 nM or less, or about 25 nM or less. Non-limiting examples of preferred binding affinity ranges for TCRs of the invention include about 1 nM to about 10 nM; about 10 nM to about 20 nM; about 20 nM to about 30 nM; about 30 nM to about 40 nM; 50 nM; about 50 nM to about 60 nM; about 60 nM to about 70 nM; about 70 nM to about 80 nM; about 80 nM to about 90 nM; and about 90 nM to about 100 nM.
與本說明書 TCR 相關,本文使用的「特異性結合」及其語法變體用於表示對 100μM 或更小的 HAVCR1-001 肽-HLA 分子複合體有結合親和力 (KD) 的 TCR。In relation to TCRs in this specification, "specific binding" and grammatical variants thereof are used herein to denote TCRs that have binding affinity (KD) for the HAVCR1-001 peptide-HLA molecule complex of 100 μM or less.
本說明書的 α/β 異二聚體 TCR可能具有其恒定結構域之間的引入二硫鍵。這種類型的優選 TCR 包括那些具有一個 TRAC 恒定域序列和 TRBC1 或 TRBC2 恒定域序列的 TCR,除非 TRAC 的蘇氨酸 48 和 TRBC1 或 TRBC2 的絲氨酸 57被半胱氨酸殘基取代,所述半胱氨酸形成 TRAC 恒定域序列和 TCR 的 TRBC1 或 TRBC2 恒定區序列之間的二硫鍵。The α/β heterodimeric TCRs of this specification may have introduced disulfide bonds between their constant domains. Preferred TCRs of this type include those having a TRAC constant domain sequence and a TRBC1 or TRBC2 constant domain sequence, unless threonine 48 of TRAC and
不論具有或不具有上述的引入鏈間鍵,本說明書的α/β 雜二聚體TCR 可能具有一個 TRAC 恒定域序列和一個 TRBC1 或 TRBC2 恒定結構域序列,並且 TRAC 恒定結構域序列和 TCR 的 TRBC1 或 TRBC2 恒定結構域序列可能透過 TRAC 外顯子 2 的 Cys4 和 TRBC1或TRBC2外顯子2 的 Cys4 之間的天然二硫鍵相連。With or without the introduced interchain linkages described above, the α/β heterodimeric TCR of this specification may have one TRAC constant domain sequence and one TRBC1 or TRBC2 constant domain sequence, and the TRAC constant domain sequence and the TRBC1 of the TCR Or the TRBC2 constant domain sequence may be linked via a natural disulfide bond between Cys4 of TRAC exon 2 and TRBC1 or Cys4 of TRBC2 exon 2.
本說明書的TCR可能包括選自由放射性核素、螢光團和生物素組成組中的可檢測標記。本說明書的TCR可能共軛至治療活性劑,如放射性核素、化學治療劑或毒素。The TCR of this specification may include a detectable label selected from the group consisting of radionuclides, fluorophores and biotin. The TCRs of this specification may be conjugated to therapeutically active agents, such as radionuclides, chemotherapeutic agents or toxins.
在一個實施方案中,具有在 α 鏈中至少一個突變和/或具有在 β 鏈中至少一個突變的 TCR 與未突變的 TCR 相比,已經修改了糖基化。In one embodiment, a TCR with at least one mutation in the alpha chain and/or with at least one mutation in the beta chain has modified glycosylation compared to an unmutated TCR.
在一個實施方案中,在TCR α 鏈和/或TCR β 鏈中包括至少一個突變的TCR對 HAVCR1-001 肽 HLA 分子複合體有結合親和力和/或結合半衰期,其是包含未突變 TCR α鏈和/或未突變 TCR β 鏈的TCR 的結合親和力的至少兩倍。腫瘤特異性 TCR 親和力增強及其開發依賴於存在最佳 TCR 親和力的窗口。這樣窗口的存在是根據觀察結果:HLA-A2 限制性病原體特異性 TCR 與 HLA-A2 限制性腫瘤相關自身抗原特異性 TCR 相比, KD 值通常大約低 10 倍。現已知,儘管腫瘤抗原可能具有免疫原性,但是因為腫瘤來自個體自身的細胞,因此僅突變蛋白質或翻譯加工改變的蛋白將被免疫系統視為外來物質。上調或過度表達(所謂的自體抗原)的抗原不一定誘導針對腫瘤的功能免疫應答:表達對這些抗原具有高度反應性的 TCR 的 T 細胞會在一種稱為中樞耐受的程序中在胸腺內被不利選擇,也就是說只有對自身抗原具有低親和力 TCR 的細胞才仍然存在。因此,本說明書的 TCR 或變體對 HAVCR1-001 的親和力可透過本領域熟知的方法來增強。In one embodiment, the TCR comprising at least one mutation in the TCR alpha chain and/or the TCR beta chain has binding affinity and/or binding half-life for the HAVCR1-001 peptide HLA molecule complex, which is a TCR comprising an unmutated TCR alpha chain and /or at least twice the binding affinity of the TCR of the unmutated TCR beta chain. Tumor-specific TCR affinity enhancement and its development depend on the existence of a window of optimal TCR affinity. The existence of such a window is based on the observation that HLA-A2-restricted pathogen-specific TCRs typically have approximately 10-fold lower KD values compared to HLA-A2-restricted tumor-associated autoantigen-specific TCRs. It is now known that although tumor antigens may be immunogenic, because tumors arise from an individual's own cells, only proteins with mutated or altered translational processing will be considered foreign by the immune system. Antigens that are upregulated or overexpressed (so-called autoantigens) do not necessarily induce a functional immune response against the tumor: T cells expressing TCRs that are highly reactive to these antigens become are unfavorably selected, that is, only cells with low affinity TCRs for self-antigens remain. Thus, the affinity of a TCR or variant of the present specification for HAVCR1-001 can be enhanced by methods well known in the art.
本說明書還涉及一種識別和分離本發明 TCR 的一種方法,所述方法包括:用 A2/HAVCR1-001 肽單體從 HLA-A*02 陰性健康供體孵育 PBMC,用四聚體-藻紅蛋白 (PE) 孵育 PBMC 並透過螢光啟動細胞分選 (FACS) – Calibur方法分析分離高親和力 T 細胞。The present specification also relates to a method of identifying and isolating the TCRs of the present invention, the method comprising: incubating PBMCs from HLA-A*02 negative healthy donors with A2/HAVCR1-001 peptide monomers, using tetramer-phycoerythrin (PE) PBMCs were incubated and high-affinity T cells were isolated by fluorescence-activated cell sorting (FACS)-Calibur assay.
本說明書還涉及一種識別和分離本發明 TCR 的一種方法,所述方法包括:獲得含整個人體 TCRαβ 基因位點 (1.1 and 0.7 Mb) 的轉基因小鼠(其T細胞表達多樣化人類 TCR,用於補償小鼠 TCR 缺乏),用 HAVCR1-001 對小鼠進行免疫處理,用四聚體 - 藻紅蛋白(PE)孵育從轉基因小鼠中獲得的PBMC,並透過螢光啟動細胞分選 (FACS) – Calibur方法分析分離高親和力T細胞。The present specification also relates to a method for identifying and isolating the TCR of the present invention, the method comprising: obtaining a transgenic mouse containing the entire human TCRαβ gene locus (1.1 and 0.7 Mb) whose T cells express diverse human TCR for to compensate for TCR deficiency in mice), mice were immunized with HAVCR1-001, PBMCs obtained from transgenic mice were incubated with tetramer-phycoerythrin (PE), and fluorescently activated cell sorting (FACS) – Calibur method analysis to isolate high-affinity T cells.
一方面,為了獲得表達本說明書 TCR 的T細胞,編碼本說明書 TCR-α和/或TCR-β 鏈的核酸被克隆入表達載體,諸如 γ 反轉錄病毒或慢病毒。重組病毒產生,然後測試功能,如抗原專一性和功能性親合力。然後,最終產品的等分試樣被用於轉導靶T細胞群體(一般純化自患者的 PBMC),在輸入患者前展開。另一方面,為了獲得表達本說明書 TCR 的T細胞,TCR RNA 透過本領域中已知的技術(例如,體外轉錄系統)合成。然後,體外合成的TCR RNA透過電穿孔來重新表達腫瘤特異性 TCR-α 和/或 TCR-β 鏈被引入獲得自健康供體的初級CD8+T細胞。In one aspect, to obtain T cells expressing the TCRs of the present disclosure, nucleic acids encoding the TCR-alpha and/or TCR-beta chains of the present disclosure are cloned into an expression vector, such as a gamma retrovirus or lentivirus. Recombinant viruses are generated and then tested for functions such as antigen specificity and functional affinity. An aliquot of the final product is then used to transduce a target T cell population (generally purified from the patient's PBMC), which is developed prior to infusion into the patient. On the other hand, to obtain T cells expressing the TCR of the present specification, TCR RNA is synthesized by techniques known in the art (eg, in vitro transcription systems). In vitro synthesized TCR RNA was then introduced into primary CD8+ T cells obtained from healthy donors by electroporation to re-express tumor-specific TCR-α and/or TCR-β chains.
為了增加表達,編碼本說明書 TCR 的核酸在操作上可連接到強啟動子,例如逆轉錄病毒長末端重複序列 (LTR)、巨細胞病毒 (CMV)、鼠幹細胞病毒 (MSCV) U3、磷酸甘油酸激酶 (PGK)、β 肌動蛋白、泛素蛋白和猿猴病毒 40 (SV40)/CD43複合啟動子、延伸因數 (EF) -1a和脾臟病灶形成病毒 (SFFV) 啟動子。在一優選實施方案中,啟動子與被表達的核酸異源。除了強啟動子外,本說明書的 TCR 表達盒可能含有附加的元素,可提高轉基因表達,包括中樞多聚嘌呤區 (CPPT), 其促進了慢病毒構建體的核易位 (Follenzi et al., 2000), 和土撥鼠肝炎病毒轉錄後調控元素 (WPRE), 其透過提高 RNA 穩定性增加轉基因表達水準 (Zufferey et al., 1999)。To increase expression, the nucleic acid encoding the TCR of this specification can be operably linked to a strong promoter, such as retroviral long terminal repeat (LTR), cytomegalovirus (CMV), murine stem cell virus (MSCV) U3, phosphoglycerate Kinase (PGK), beta-actin, ubiquitin protein, and Simian virus 40 (SV40)/CD43 composite promoter, elongation factor (EF)-1a, and spleen foci-forming virus (SFFV) promoter. In a preferred embodiment, the promoter is heterologous to the nucleic acid being expressed. In addition to strong promoters, the TCR expression cassettes of this specification may contain additional elements that enhance transgene expression, including the central polypurine region (CPPT), which facilitates nuclear translocation of lentiviral constructs (Follenzi et al., 2000), and woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), which increases transgene expression levels by enhancing RNA stability (Zufferey et al., 1999).
本發明 TCR 的 α 和 β 鏈可由位於分開的載體核酸進行編碼,或者可透過位於同一載體的多核苷酸編碼。The alpha and beta strands of the TCRs of the invention may be encoded by separate vector nucleic acids, or may be encoded by polynucleotides located in the same vector.
實現高水準的 TCR 表面表達需要引入 TCR 的 TCR-α 和 TCR-β 鏈高水準轉錄。為了實現它,本說明書的 TCR-α 和 TCR-β 鏈可在單一的載體中被克隆入雙順反子構建體,其已被證明能夠克服這一障礙。使用 TCR-α 和 TCR-β 鏈在之間的病毒核糖體間進入位元點 (IRES) 導致兩鏈的協同表達,因為 TCR-α 和 TCR-β 鏈均由在翻譯過程中分成兩個蛋白質的單一轉錄物產生,從而確保了產生 TCR-α 和 TCR-β 鏈的相等摩爾比。(Schmitt et al. 2009)。Achieving high levels of TCR surface expression requires high levels of transcription of the TCR-α and TCR-β chains of the introduced TCR. To achieve this, the TCR-alpha and TCR-beta chains of this specification can be cloned in a single vector into a bicistronic construct, which has been shown to overcome this obstacle. The use of the viral interribosome entry site (IRES) between the TCR-alpha and TCR-beta chains results in the co-expression of the two chains, since both the TCR-alpha and TCR-beta chains are split into two proteins during translation A single transcript is produced, thus ensuring equal molar ratios of TCR-α and TCR-β chains are produced. (Schmitt et al. 2009).
編碼本說明書 TCR 的核酸可以是被優化以從宿主細胞增加表達的密碼子。遺傳密碼冗餘讓一些氨基酸被一個以上的密碼子編碼,但某些密碼子沒有其他密碼子「優化」,因為匹配 tRNA 以及其他因數的相對可用性 (Gustafsson et al., 2004)。修改 TCR-α 和 TCR-β 基因序列使得每個氨基酸被用於哺乳動物基因表達的最佳密碼子編碼,以及消除 mRNA 不穩定性基序或隱蔽剪接位元點,已顯示可顯著提高 TCR-α 和 TCR-β 基因表達 (Scholten et al., 2006)。Nucleic acids encoding the TCRs of the present specification may be codon optimized for increased expression from host cells. Genetic code redundancy allows some amino acids to be encoded by more than one codon, but some codons are not "optimized" for others because of the relative availability of matching tRNAs as well as other factors (Gustafsson et al., 2004). Modifying the TCR-α and TCR-β gene sequences so that each amino acid is encoded by optimal codons for mammalian gene expression, as well as eliminating mRNA instability motifs or cryptic splice sites, has been shown to significantly increase TCR- Alpha and TCR-beta gene expression (Scholten et al., 2006).
此外,引入的和內源性 TCR 鏈之間的錯配可能會導致獲得特異性,其構成自身免疫的顯著風險。例如,混合 TCR 二聚體的形成可能會減少可用以形成正確配對 TCR 複合體的 CD3 分子數目,因此,可以顯著降低表達所引入 TCR的細胞的功能性親合力 (Kuball et al., 2007)。Furthermore, mismatches between the introduced and endogenous TCR chains may lead to the acquisition of specificity, which poses a significant risk of autoimmunity. For example, the formation of mixed TCR dimers may reduce the number of CD3 molecules available to form correctly paired TCR complexes and, therefore, can significantly reduce the functional affinity of cells expressing the introduced TCR (Kuball et al., 2007).
為了減少錯配,本說明書引入的 TCR 鏈的 C-末端結構域可以進行修改以促進鏈間親和力,同時降低引入鏈與內源 TCR 配對的能力。這些策略可能包括用鼠配對物取代人類 TCR-α 和 TCR-β C端結構域(鼠化 C 端結構域);透過引入第二個半胱氨酸殘基到引入 TCR 的 TCR-α 和 TCR-β 鏈產生 C 末端結構域的第二個鏈間二硫鍵(半胱氨酸修飾);交換 TCR-α 和 TCR-β 鏈 C 端結構域的相互作用殘基(「杵臼結構」);直接融合 TCR-α和 TCR-β 鏈可變結構域至 CD3ζ(CD3ζ 融合)(Schmitt et al. 2009)。To reduce mismatches, the C-terminal domains of the TCR chains introduced in this specification can be modified to promote interchain affinity while reducing the ability of the introduced chains to pair with endogenous TCRs. These strategies may include replacement of the human TCR-α and TCR-β C-terminal domains with murine counterparts (murine C-terminal domains); introduction of a second cysteine residue to the TCR-α and TCR-introduced TCR by introducing a second cysteine residue - β chain creates a second interchain disulfide bond in the C-terminal domain (cysteine modification); swaps the interacting residues of the C-terminal domains of TCR-α and TCR-β chains ("knob-hole structure"); Direct fusion of TCR-alpha and TCR-beta chain variable domains to CD3ζ (CD3ζ fusion) (Schmitt et al. 2009).
在一實施方案中,宿主細胞被改變結構以表達本說明書的 TCR。在一優選實施方案中,宿主細胞為人T細胞或T細胞祖細胞。在一些實施方案中,T 細胞或T細胞祖細胞從癌症患者中獲得。在另一些實施方案中,T 細胞或T細胞祖細胞從健康供體中獲得。本說明書的宿主細胞相對於待治療的患者可以為同種異體或自體的。在一實施方案中,宿主是被轉化以表達 α/β TCR 的 γ/δ T 細胞。In one embodiment, the host cell is altered to express a TCR of the present specification. In a preferred embodiment, the host cells are human T cells or T cell progenitor cells. In some embodiments, the T cells or T cell progenitor cells are obtained from a cancer patient. In other embodiments, the T cells or T cell progenitors are obtained from healthy donors. The host cells of the present specification may be allogeneic or autologous to the patient to be treated. In one embodiment, the host is a gamma/delta T cell transformed to express an alpha/beta TCR.
「藥物組合物」是指適合在醫療機構用於人體的組合物。優選地,藥物組合物為無菌狀態,並根據 GMP 指南生產。"Pharmaceutical composition" refers to a composition suitable for use in humans in a medical setting. Preferably, the pharmaceutical composition is sterile and manufactured according to GMP guidelines.
藥物組合物包括游離形式或以一種藥用鹽形式存在的肽(也參見上文)。此處使用的「藥用鹽」系指所公開的肽的一種衍生物,其中該肽由制酸或藥劑的堿鹽進行改性。例如,用與適合的酸反應的游離堿(通常其中的中性藥物有一個中性–NH 2基團)製備酸式鹽。適合製備酸鹽的酸包括有機酸,如:乙酸、丙酸、羥基酸、丙酮酸、草酸、蘋果酸、丙二酸、丁二酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸酸、肉桂酸、扁桃酸、甲磺酸、甲磺酸、苯磺酸、水楊酸等等、以及無機酸,如:鹽酸、氫溴酸、硫酸、硝酸和磷酸等。相反,可在一種肽上表現的酸性基團的堿鹽製劑使用藥用堿基進行製備,如氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣、三甲胺等等。 Pharmaceutical compositions include the peptides in free form or as a pharmaceutically acceptable salt (see also above). "Pharmaceutically acceptable salt" as used herein refers to a derivative of the disclosed peptide wherein the peptide is modified with a salt of an antacid or an agent. For example, acid salts are prepared from free phosphoniums (usually in which the neutral drug has a neutral -NH 2 group) reacted with a suitable acid. Acids suitable for the preparation of acid salts include organic acids such as: acetic acid, propionic acid, hydroxy acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzene Formic acid, cinnamic acid, mandelic acid, methanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, etc., and inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. In contrast, halide salt formulations of acidic groups that can be represented on a peptide are prepared using pharmaceutically acceptable halide groups, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, and the like.
在特別優選的實施方案中,藥物組合物包括乙酸(醋酸鹽),三氟乙酸鹽或鹽酸(氯化物)形式的肽。In a particularly preferred embodiment, the pharmaceutical composition comprises the peptide in the form of acetic acid (acetate), trifluoroacetate or hydrochloric acid (chloride).
本發明中所述的藥劑優選為一種免疫治療藥劑,例如,一種疫苗。該疫苗可直接給到患者的受影響器官,也可i.d.、i.m.、s.c.、i.p. 和 i.v. 注射方式全身給藥,或體外應用到來自患者或其細胞株的細胞(隨後再將這些細胞注入到患者中),或體外用於從來自患者的免疫細胞的一個細胞亞群(然後再將細胞重新給予患者)。如果核酸體外注入細胞,可能有益於細胞轉染,以共同表達免疫刺激細胞因數(如白細胞介素-2)。肽可完全單獨給藥,也可與免疫刺激佐劑相結合(見下文)、或與免疫刺激細胞因數聯合使用、或以適當的輸送系統給藥(例如脂質體)。該肽也可共軛形成一種合適的載體(如鑰孔蟲戚血藍蛋白 (KLH) 或甘露)到合適的載體 (參閱WO 95/18145 及 (Longenecker et al., 1993))。肽也可能被標記,可能是融合蛋白,或可能是雜交分子。在本發明中給出序列的肽預計能刺激 CD4 或 CD8 T細胞。然而,在有 CD4 T-輔助細胞的幫助時,CD8 T細胞刺激更加有效。因此,對於刺激 CD8 T 細胞的 MHC-I 類表位,一種雜合分子的融合夥伴或片段提供了刺激 CD4 陽性 T 細胞的適當表位。CD4- 和 CD8 刺激表位為本領域所熟知、並包括本發明中確定的表位。The agent described in the present invention is preferably an immunotherapeutic agent, eg, a vaccine. The vaccine can be administered directly to the affected organ of the patient, administered systemically by i.d., i.m., s.c., i.p. and i.v. ), or in vitro for a subset of cells derived from immune cells from a patient (the cells are then re-administered to the patient). If the nucleic acid is injected into cells in vitro, it may be beneficial to transfect cells to co-express immunostimulatory cytokines (eg, interleukin-2). The peptides can be administered entirely alone, or in combination with immunostimulatory adjuvants (see below), or in combination with immunostimulatory cytokines, or in a suitable delivery system (eg, liposomes). The peptide can also be conjugated to a suitable carrier such as keyhole limpet hemocyanin (KLH) or manna (see WO 95/18145 and (Longenecker et al., 1993)). Peptides may also be labeled, may be fusion proteins, or may be hybrid molecules. The peptides of the sequences given in the present invention are expected to stimulate CD4 or CD8 T cells. However, CD8 T cell stimulation was more effective when assisted by CD4 T-helper cells. Thus, for MHC class I epitopes that stimulate CD8 T cells, a fusion partner or fragment of a hybrid molecule provides the appropriate epitope to stimulate CD4 positive T cells. CD4- and CD8 stimulating epitopes are well known in the art and include the epitopes identified in the present invention.
一方面,疫苗包括至少含有 SEQ ID NO:1 至 SEQ ID NO:161 中提出的一種肽以及至少另外一種肽,優選為 2 至 50 個、更優選為 2 至 25 個、再優選為 2 至 20 個、最優選為 2、3、4、5、6、7、8、9、10、11、12 、13、14、15、16、17 或 18 個肽。肽可能從一個或多個特定 TAA 中衍生,並且可能與 MHC I 類分子結合。In one aspect, the vaccine comprises at least one peptide set forth in SEQ ID NO: 1 to SEQ ID NO: 161 and at least one other peptide, preferably 2 to 50, more preferably 2 to 25, still more preferably 2 to 20 and most preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 peptides. Peptides may be derived from one or more specific TAAs and may bind to MHC class I molecules.
另一方面,本發明提出了一種編碼本發明中肽或肽變體的核酸(如多聚核苷酸)。多聚核苷酸可能為,例如,DNA、cDNA、PNA、RNA 或其組合物,它們可為單鏈和/或雙鏈、或多聚核苷酸的原生或穩定形式(如:具有硫代磷酸骨架的多聚核苷酸),並且只要它編碼肽,就可能包含也可能不包含內含子。當然,多聚核苷酸只能編碼加入天然肽鍵並含有天然氨基酸殘基的肽。另一個方面,本發明提出了一種可根據本發明表達多肽的表達載體。In another aspect, the present invention provides a nucleic acid (eg, a polynucleotide) encoding a peptide or peptide variant of the present invention. Polynucleotides may be, for example, DNA, cDNA, PNA, RNA, or combinations thereof, which may be single- and/or double-stranded, or native or stable forms of polynucleotides (eg, with thiols phosphate backbone polynucleotide), and may or may not contain introns as long as it encodes a peptide. Of course, polynucleotides can only encode peptides that incorporate natural peptide bonds and contain natural amino acid residues. In another aspect, the present invention provides an expression vector that can express a polypeptide according to the present invention.
對於連接多核苷酸,已經開發出多種方法,尤其是針對 DNA,可通過向載體補充可連接性末端等方法進行連接。例如,可向 DNA 片段加入補充性均聚物軌道,之後 DNA 片段被插入到載體 DNA。然後,通過補充性均聚物尾巴的氫鍵結合,將載體和 DNA 片段結合,從而形成重組 DNA 分子。For ligating polynucleotides, various methods have been developed, especially for DNA, such as by supplementing the vector with ligable ends. For example, complementary homopolymer tracks can be added to the DNA fragment, which is then inserted into the vector DNA. The vector and DNA fragments are then joined by hydrogen bonding of complementary homopolymer tails to form a recombinant DNA molecule.
含有一個或多個酶切位點的合成接頭為 DNA 片段與載體連接提供了另一種方法。含各種限制性核酸內切酶的合成接頭可通過多種管道購得,其中包括從國際生物技術公司(International Biotechnologies Inc, New Haven, CN, 美國)購得。Synthetic linkers containing one or more restriction sites provide an alternative method for ligating DNA fragments to vectors. Synthetic linkers containing various restriction endonucleases are commercially available through a variety of sources, including from International Biotechnologies Inc, New Haven, CN, USA.
編碼本發明多肽的 DNA 理想修飾方法是使用 Saiki 等人 (Saiki et al., 1988) 所採用的聚合酶鏈反應方法。此方法可用於將 DNA 引入合適的載體(例如,通過設計合適的酶切位點),也可用於本領域已知的其他有用方法修飾 DNA。如果使用病毒載體,痘病毒載體或腺病毒載體為優選。A desirable method of modification of the DNA encoding the polypeptides of the present invention is to use the polymerase chain reaction method employed by Saiki et al. (Saiki et al., 1988). This method can be used to introduce DNA into a suitable vector (eg, by designing suitable restriction sites), and can also be used to modify DNA by other useful methods known in the art. If a viral vector is used, a poxvirus vector or an adenovirus vector is preferred.
之後,DNA (或在逆轉錄病毒載體情況下,RNA)可能表達於合適的宿主,從而製成含本發明肽或變體的多肽。因此,可根據已知技術使用編碼本發明肽或變體的 DNA,用本文所述方法適當修飾後,構建表達載體,然後表達載體用於轉化合適宿主細胞,從而表達和產生本發明中的多肽。此類技術包括那些公開於,例如,美國專利 4,440,859、4,530,901、4,582,800、4,677,063、4,678,751、4,704,362、4,710,463、4,757,006、4,766,075 和 4,810,648。The DNA (or RNA in the case of retroviral vectors) may then be expressed in a suitable host to produce a polypeptide containing the peptide or variant of the invention. Thus, the polypeptides of the invention can be expressed and produced according to known techniques using DNA encoding the peptides or variants of the invention, suitably modified by the methods described herein, to construct expression vectors, which are then used to transform suitable host cells . Such techniques include those disclosed in, for example, U.S. Patent Nos. 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075, and 4,810,648.
編碼含本發明化合物多肽的 DNA (或在逆轉錄病毒載體情況下,RNA)可能被加入到其他多種 DNA 序列,從而引入到合適的宿主中。同伴 DNA 將取決於宿主的性質、DNA 引入宿主的方式、以及是否需要保持為游離體還是要相互結合。DNA (or RNA, in the case of retroviral vectors) encoding polypeptides containing the compounds of the present invention may be incorporated into various other DNA sequences for introduction into suitable hosts. Companion DNA will depend on the nature of the host, how the DNA was introduced into the host, and whether it needs to remain episomal or bind to each other.
一般來說,DNA 可以適當的方向和正確的表達閱讀框架附著到一種表達載體(如質粒)中。如有必要,該 DNA 可能與所需宿主所識別的相應轉錄和翻譯調節控制核苷酸序列連接,儘管表達載體中一般存在此類控制功能。然後,該載體通過標準方法被引入宿主。一般來說,並不是所有的宿主都會被載體轉化。因此,有必要選擇轉化過的宿主細胞。選擇方法包括用任何必要的控制元素向表達載體插入一個 DNA 序列,該序列對轉化細胞中的可選擇性屬性(如抗生素耐藥性)進行編碼。In general, DNA can be attached to an expression vector (such as a plasmid) in the proper orientation and in the correct reading frame for expression. If necessary, the DNA may be ligated with corresponding transcriptional and translational regulatory control nucleotide sequences recognized by the desired host, although such control functions are typically present in expression vectors. The vector is then introduced into the host by standard methods. In general, not all hosts will be transformed with the vector. Therefore, it is necessary to select transformed host cells. Selection methods include inserting into the expression vector a DNA sequence encoding a selectable attribute, such as antibiotic resistance, in transformed cells with any necessary control elements.
另外,有這種選擇屬性的基因可在另外一個載體上,該載體用來協同轉化所需的宿主細胞。Alternatively, the gene with this selective property can be on another vector that is used to cooperatively transform the desired host cell.
然後,本發明中的重組 DNA 所轉化的宿主細胞在本文中所述本領域技術人員熟悉的合適條件下培養足夠長的時間,從而表達之後可回收的肽。The host cells transformed with the recombinant DNA of the present invention are then cultured under suitable conditions familiar to those skilled in the art described herein for a period of time sufficient to express the peptides which can then be recovered.
有許多已知的表達系統,包括細菌(如大腸桿菌和枯草芽孢桿菌)、酵母(如酵母菌)、絲狀真菌(如曲黴菌)、植物細胞、動物細胞及昆蟲細胞。該系統可優選為哺乳動物細胞,如來自 ATCC 細胞生物學庫 (Cell Biology Collection) 中的 CHO 細胞。There are many known expression systems, including bacteria (eg, Escherichia coli and Bacillus subtilis), yeast (eg, yeast), filamentous fungi (eg, Aspergillus), plant cells, animal cells, and insect cells. The system may preferably be mammalian cells, such as CHO cells from the ATCC Cell Biology Collection.
典型的哺乳動物細胞組成型表達載體質粒包括 CMV 或含一個合適的多聚 A 尾巴的 SV40 啟動子以及抗性標誌物(如新黴素)。一個實例為從 Pharmacia 公司(Piscataway,新澤西,美國)獲得的 pSVL。一種可誘導型哺乳動物表達載體的例子是 pMSG,也可以從 Pharmacia 公司獲得。有用的酵母質粒載體是 pRS403-406 和 pRS413-416,一般可從 Stratagene Cloning Systems 公司(La Jolla, CA 92037,美國)獲得。質粒 pRS403、pRS404、pRS405 和 pRS406 是酵母整合型質粒 (YIp),並插入了酵母可選擇性標記物 HIS3、TRP1、LEU2 和 URA3。pRS413-416 質粒為酵母著絲粒質粒 (Ycp)。基於 CMV 啟動子的載體(如,來自於 Sigma-Aldrich 公司)提供了暫態或穩定的表達、胞漿表達或分泌,以及 FLAG、3xFLAG、c-myc 或 MATN 不同組合物中的 N-端或 C-端標記。這些融合蛋白可用於檢測、純化及分析重組蛋白。雙標融合為檢測提供了靈活性。Typical constitutive expression vector plasmids for mammalian cells include CMV or the SV40 promoter with a suitable poly-A tail and resistance markers such as neomycin. An example is pSVL obtained from Pharmacia Corporation (Piscataway, NJ, USA). An example of an inducible mammalian expression vector is pMSG, also available from Pharmacia. Useful yeast plasmid vectors are pRS403-406 and pRS413-416, generally available from Stratagene Cloning Systems (La Jolla, CA 92037, USA). Plasmids pRS403, pRS404, pRS405 and pRS406 are yeast integrating plasmids (YIp) with insertion of the yeast selectable markers HIS3, TRP1, LEU2 and URA3. The pRS413-416 plasmid is a yeast centromeric plasmid (Ycp). CMV promoter-based vectors (eg, from Sigma-Aldrich) provide transient or stable expression, cytoplasmic expression or secretion, and N-terminal or C-terminal labeling. These fusion proteins can be used for detection, purification and analysis of recombinant proteins. Dual-label fusion provides flexibility for detection.
強勁的人巨細胞病毒 (CMV) 啟動子調控區使得 COS 細胞中的組成蛋白表達水準高達 1 mg/L。對於較弱的細胞株,蛋白水準一般低於 0.1 mg/L。SV40 複製原點的出現將導致 DNA 在 SV40 複製容納性 COS 細胞中高水準複製。例如,CMV 載體可包含細菌細胞中的 pMB1(pBR322 的衍生物)複製原點、細菌中進行氨苄青黴素抗性選育的 鈣-內醯胺酶基因、hGH polyA 和 f1 的原點。含前胰島素原引導 (PPT) 序列的載體可使用抗 FLAG 抗體、樹脂和板引導 FLAG 融合蛋白分泌到進行純化的培養基中。其他與各種宿主細胞一起應用的載體和表達系統是本領域熟知眾所周知的。The robust human cytomegalovirus (CMV) promoter regulatory region enables expression of constitutive proteins up to 1 mg/L in COS cells. For weaker cell lines, protein levels are generally below 0.1 mg/L. The emergence of the SV40 origin of replication will lead to high levels of DNA replication in SV40 replication-compatible COS cells. For example, a CMV vector may contain the pMB1 (derivative of pBR322) origin of replication in bacterial cells, the calcium-lactamase gene for ampicillin resistance selection in bacteria, the origin of hGH polyA and f1. A vector containing a preproinsulin leader (PPT) sequence can be used to direct secretion of FLAG fusion proteins into the medium for purification using anti-FLAG antibodies, resins, and plates. Other vectors and expression systems for use with various host cells are well known in the art.
在另一個實施方案中,對本發明的兩個或更多的肽或肽變體進行編碼,因此,以一個連續順序(類似於「一串珠子」的構建體)表達。在達到目標,所述肽或肽變體可能通過連接子氨基酸的延伸處(例如LLLLLL)連接或融合一起,也可能他們之間沒有任何附加的肽而被連接。這些構建體也可用於癌症治療,可誘導涉及 MHC I 和 MHC II 類分子的免疫應答。In another embodiment, two or more peptides or peptide variants of the invention are encoded and, thus, expressed in a contiguous order (analogous to a "string of beads" construct). Upon reaching the goal, the peptides or peptide variants may be linked or fused together by extension of linker amino acids (eg LLLLLL), or they may be linked without any additional peptide between them. These constructs can also be used in cancer therapy to induce immune responses involving MHC class I and MHC class II molecules.
本發明還涉及一種宿主細胞,其以本發明的多核苷酸載體構建轉化而來。宿主細胞可為原核細胞,也可為真核細胞。在有些情況下,細菌細胞為優選原核宿主細胞,典型為大腸桿菌株,例如,大腸桿菌菌株 DH5(從 Bethesda Research Laboratories 公司(Bethesda, MD, 美國)獲得)和 RR1(從美國菌種保藏中心(ATCC, Rockville, MD, 美國),ATCC 編號31343 獲得)。首選的真核宿主細胞包括酵母、昆蟲和哺乳動物細胞,優選為脊椎動物細胞,如:小鼠、大鼠、猴子或人成纖維細胞和結腸癌細胞株中的細胞。酵母宿主細胞包括 YPH499、YPH500 和 YPH501,一般可從 Stratagene Cloning Systems 公司(La Jolla, CA 92037, 美國)獲得。首選哺乳動物宿主細胞包括中國倉鼠卵巢 (CHO) 細胞為 ATCC 中的 CCL61 細胞、NIH 瑞士小鼠胚胎細胞 NIH/3T3 為 ATCC 中的 CRL 1658 細胞、猴腎源性 COS-1 細胞為 ATCC 中的 CRL 1650 細胞以及人胚胎腎細胞的 293 號細胞。首選昆蟲細胞為 Sf9 細胞,可用杆狀病毒表達載體轉染。有關針對表達選擇合適宿主細胞的概要,可從教科書 (Paulina Balbás and Argelia Lorence 《Methods in Molecular Biology Recombinant Gene Expression, Reviews and Protocols》Part One, Second Edition, ISBN 978-1-58829-262-9) 和技術人員知道的其他文獻中查到。The present invention also relates to a host cell transformed with the polynucleotide vector of the present invention. Host cells can be prokaryotic cells or eukaryotic cells. In some cases, bacterial cells are preferably prokaryotic host cells, typically E. coli strains, eg, E. coli strains DH5 (obtained from Bethesda Research Laboratories, MD, USA) and RR1 (obtained from the American Type Culture Collection ( ATCC, Rockville, MD, USA), obtained with ATCC No. 31343). Preferred eukaryotic host cells include yeast, insect and mammalian cells, preferably vertebrate cells such as mouse, rat, monkey or human fibroblasts and cells in colon cancer cell lines. Yeast host cells include YPH499, YPH500 and YPH501, generally available from Stratagene Cloning Systems (La Jolla, CA 92037, USA). Preferred mammalian host cells include Chinese hamster ovary (CHO) cells as CCL61 cells in ATCC, NIH Swiss mouse embryonic cells NIH/3T3 as CRL 1658 cells in ATCC, monkey kidney-derived COS-1 cells as CRL in ATCC 1650 cells and 293 cells of human embryonic kidney cells. The preferred insect cells are Sf9 cells, which can be transfected with baculovirus expression vectors. An outline for selecting suitable host cells for expression can be found in textbooks (Paulina Balbás and Argelia Lorence "Methods in Molecular Biology Recombinant Gene Expression, Reviews and Protocols" Part One, Second Edition, ISBN 978-1-58829-262-9) and found in other literature known to the skilled person.
含本發明 DNA 結構的適當宿主細胞的轉化可使用大家熟知的方法完成,通常取決於使用載體的類型。關於原核宿主細胞的轉化,請參見,例如,Cohen 等人的文獻 (Cohen et al., 1972) 和 (Green and Sambrook, 2012)。酵母細胞的轉化在 Sherman 等人的文章 (Sherman et al., 1986) 中進行了描述。Beggs (Beggs, 1978) 中所述的方法也很有用。對於脊椎動物細胞,轉染這些細胞的試劑等,例如,磷酸鈣和 DEAE-葡聚糖或脂質體配方,可從 Stratagene Cloning Systems 公司或 Life Technologies 公司(Gaithersburg, MD 20877,美國)獲得。電穿孔也可用於轉化和/或轉染細胞,是本領域用於轉化酵母細胞、細菌細胞、昆蟲細胞和脊椎動物細胞大家熟知的方法。Transformation of suitable host cells containing the DNA constructs of the present invention can be accomplished using well-known methods, generally depending on the type of vector used. For transformation of prokaryotic host cells, see, for example, Cohen et al. (Cohen et al., 1972) and (Green and Sambrook, 2012). Transformation of yeast cells is described in Sherman et al. (Sherman et al., 1986). The method described in Beggs (Beggs, 1978) is also useful. For vertebrate cells, reagents and the like for transfection of these cells, eg, calcium phosphate and DEAE-dextran or liposomal formulations, are available from Stratagene Cloning Systems or Life Technologies (Gaithersburg, MD 20877, USA). Electroporation can also be used to transform and/or transfect cells and is a method well known in the art for transforming yeast cells, bacterial cells, insect cells and vertebrate cells.
被成功轉化的細胞(即含本發明 DNA 結構的細胞)可用大家熟知的方法(如 PCR)進行識別。另外,上清液存在的蛋白可使用抗體進行檢測。Successfully transformed cells (ie, cells containing the DNA constructs of the present invention) can be identified by well-known methods such as PCR. Alternatively, proteins present in the supernatant can be detected using antibodies.
應瞭解,本發明中的某些宿主細胞用於製備本發明中的肽,例如細菌細胞、酵母細胞和昆蟲細胞。但是,其他宿主細胞可能對某些治療方法有用。例如,抗原表現細胞(如樹突狀細胞)可用于表達本發明中的肽,使他們可以加載入相應的 MHC 分子中。因此,本發明提出了含本發明中核酸或表達載體的一種宿主細胞。It will be appreciated that certain host cells of the present invention are used to prepare the peptides of the present invention, such as bacterial cells, yeast cells and insect cells. However, other host cells may be useful for some treatments. For example, antigen-expressing cells such as dendritic cells can be used to express the peptides of the invention so that they can be loaded into the corresponding MHC molecules. Accordingly, the present invention proposes a host cell containing the nucleic acid or expression vector of the present invention.
在一個優選實施方案中,宿主細胞為抗原表現細胞,尤其是樹突狀細胞或抗原表現細胞。2010 年 4 月 29 日,美國食品和藥物管理局 (FDA) 批准載有含攝護腺酸性磷酸酶 (PAP) 的重組融合蛋白之APC可用於治療無症狀或症狀輕微的轉移性 HRPC (Rini et al., 2006; Small et al., 2006)。In a preferred embodiment, the host cells are antigen-expressing cells, especially dendritic cells or antigen-expressing cells. On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved APC containing a recombinant fusion protein containing prostate acid phosphatase (PAP) for the treatment of asymptomatic or mildly symptomatic metastatic HRPC (Rini et al. al., 2006; Small et al., 2006).
另一方面,本發明提出了一種配製一種肽及其變體的方法,該方法包括培養宿主細胞和從宿主細胞或其培養基中分離肽。In another aspect, the present invention provides a method of formulating a peptide and variants thereof, the method comprising culturing a host cell and isolating the peptide from the host cell or its culture medium.
在另一個實施方案中,本發明中的肽、核酸或表達載體用於藥物中。例如,肽或其變體可製備為靜脈 (i.v.) 注射劑、皮下 (s.c.) 注射劑、皮內 (i.d.) 注射劑、腹膜內 (i.p.) 注射劑、肌肉 (i.m.) 注射劑。肽注射的優選方法包括 s.c.、i.d.、i.p.、i.m. 和 i.v. 注射。DNA 注射的優選方法為 i.d.、i.m.、s.c.、i.p. 和 i.v. 注射。例如,給予 50 µg 至 1.5 mg,優選為 125 µg 至 500 µg 的肽或 DNA,這取決於具體的肽或 DNA。上述劑量範圍在以前的試驗中成功使用 (Walter et al., 2012)。In another embodiment, the peptides, nucleic acids or expression vectors of the present invention are used in medicine. For example, the peptides or variants thereof can be prepared as intravenous (i.v.) injections, subcutaneous (s.c.) injections, intradermal (i.d.) injections, intraperitoneal (i.p.) injections, intramuscular (i.m.) injections. Preferred methods of peptide injection include s.c., i.d., i.p., i.m. and i.v. injections. Preferred methods of DNA injection are i.d., i.m., s.c., i.p. and i.v. injections. For example, 50 µg to 1.5 mg, preferably 125 µg to 500 µg of peptide or DNA is administered, depending on the specific peptide or DNA. The above dose range has been used successfully in previous trials (Walter et al., 2012).
用於主動免疫接種的多聚核苷酸可為基本純化形式,也可包被於載體或輸送系統。核酸可能為 DNA、cDNA、PNA、RNA,也可能為其組合物。這種核酸的設計和引入方法為本領域所熟知。例如,文獻中有其概述 (Teufel et al., 2005)。多核苷酸疫苗很容易製備,但這些載體誘導免疫反應的作用模式尚未完全瞭解。合適的載體和輸送系統包括病毒 DNA 和/或 RNA,如基於腺病毒、牛痘病毒、逆轉錄病毒、皰疹病毒、腺相關病毒或含一種以上病毒元素的混合病毒的系統。非病毒輸送系統包括陽離子脂質體和陽離子聚合物,是 DNA 輸送所屬領域內熟知的系統。也可使用物理輸送系統,如通過「基因槍」。肽或核酸編碼的肽可以是一種融合蛋白,例如,含刺激 T 細胞進行上述 CDR 的表位。The polynucleotides used for active immunization can be in substantially purified form, or they can be coated on a carrier or delivery system. Nucleic acids may be DNA, cDNA, PNA, RNA, or combinations thereof. Methods for the design and introduction of such nucleic acids are well known in the art. For example, it is outlined in the literature (Teufel et al., 2005). Polynucleotide vaccines are readily prepared, but the mode of action of these vectors to induce immune responses is not fully understood. Suitable vectors and delivery systems include viral DNA and/or RNA, such as systems based on adenovirus, vaccinia virus, retrovirus, herpes virus, adeno-associated virus, or mixed viruses containing more than one viral element. Non-viral delivery systems, including cationic liposomes and cationic polymers, are systems well known in the art for DNA delivery. Physical delivery systems, such as via a "gene gun", may also be used. The peptide or nucleic acid-encoded peptide may be a fusion protein, eg, containing epitopes that stimulate T cells to perform the above-mentioned CDRs.
本發明的藥劑也可能包括一種或多種佐劑。佐劑是那些非特異性地增強或加強免疫反應的物質(例如,通過 CD8-陽性 T 細胞和輔助 T(T H) 細胞介導的對一種抗原的免疫應答,因此被視為對本發明的藥劑有用。適合的佐劑包括(但不僅限於)1018ISS、鋁鹽、AMPLIVAX ®、AS15、BCG、CP-870,893、CpG7909、CyaA、dSLIM、鞭毛蛋白或鞭毛蛋白衍生的 TLR5 配體、FLT3 配體、GM-CSF、IC30、IC31、咪喹莫特 (ALDARA ®)、resiquimod、ImuFact IMP321、白細胞介素 IL-2、IL-13、IL-21、干擾素 α 或 β,或其聚乙二醇衍生物、IS Patch、ISS、ISCOMATRIX、ISCOMs、JuvImmune ®、LipoVac、MALP2、MF59、單磷醯脂A、Montanide IMS 1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA-51、水包油和油包水乳狀液、OK-432、OM-174、OM-197-MP-EC、ONTAK、OspA、PepTel® 載體系統、基於聚丙交酯複合乙交酯 [PLG] 和右旋糖苷微粒、重組人乳鐵傳遞蛋白 SRL172、病毒顆粒和其他病毒樣顆粒、YF-17D、VEGF trap、R848、β-葡聚糖、Pam3Cys、源自皂角苷、分支桿菌提取物和細菌細胞壁合成模擬物的 Aquila 公司的 QS21 刺激子,以及其他專有佐劑,如:Ribi's Detox、Quil 或 Superfos。優選佐劑如:弗氏佐劑或 GM-CSF。前人對一些樹突狀細胞特異性免疫佐劑(如 MF59)及其製備方法進行了描述 (Allison and Krummel, 1995)。也可能使用細胞因數。一些細胞因數直接影響樹突狀細胞向淋巴組織遷移(如,TNF-),加速樹突狀細胞成熟為 T 淋巴細胞的有效抗原表現細胞(如,GM-CSF、IL-1 和 IL-4)(美國 5849589號專利,特別以其完整引用形式併入本文),並充當免疫佐劑(如 IL-12、IL-15、IL-23、IL-7、IFN-α、IFN-β) (Gabrilovich et al., 1996)。 The agents of the present invention may also include one or more adjuvants. Adjuvants are those substances that non-specifically enhance or potentiate an immune response (eg, an immune response to an antigen mediated by CD8-positive T cells and helper T( TH ) cells, and are therefore considered to be responsive to the agents of the present invention. Useful. Suitable adjuvants include, but are not limited to, 1018ISS, aluminum salts, AMPLIVAX® , AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagellin or flagellin-derived TLR5 ligands, FLT3 ligands, GM - CSF, IC30, IC31, imiquimod (ALDARA ® ), resiquimod, ImuFact IMP321, interleukin IL-2, IL-13, IL-21, interferon alpha or beta, or a polyethylene glycol derivative thereof , IS Patch, ISS, ISCOMATRIX, ISCOMs, JuvImmune ® , LipoVac, MALP2, MF59, Monophosphoric Acid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, Oil-in-Water and Water-in-Oil Emulsion Liquid, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® carrier systems, polylactide complex glycolide [PLG] and dextran based microparticles, recombinant human lactoferrin delivery Protein SRL172, viral particles and other virus-like particles, YF-17D, VEGF trap, R848, β-glucan, Pam3Cys, Aquila's QS21 stimulation derived from saponins, mycobacterial extracts and bacterial cell wall synthesis mimics Adjuvants, and other proprietary adjuvants such as Ribi's Detox, Quil or Superfos. Preferred adjuvants such as Freund's adjuvant or GM-CSF. Some dendritic cell-specific immune adjuvants (such as MF59) and Its preparation is described (Allison and Krummel, 1995). Cytokines may also be used. Some cytokines directly affect dendritic cell migration to lymphoid tissue (eg, TNF-), accelerating dendritic cell maturation into T lymphocytes potent antigen-expressing cells (eg, GM-CSF, IL-1, and IL-4) (US Pat. No. 5,849,589, specifically incorporated herein by reference in its entirety), and act as immune adjuvants (eg, IL-12, IL- 15. IL-23, IL-7, IFN-α, IFN-β) (Gabrilovich et al., 1996).
據報告,CpG 免疫刺激寡核苷酸可提高佐劑在疫苗中的作用。如果沒有理論的約束, CpG 寡核苷酸可通過 Toll 樣受體 (TLR) (主要為 TLR9)啟動先天(非適應性)免疫系統從而起作用。CpG 引發的 TLR9 活化作用提高了對各種抗原的抗原特異性體液和細胞反應,這些抗原包括肽或蛋白抗原、活病毒或被殺死的病毒、樹突狀細胞疫苗、自體細胞疫苗以及預防性和治療性疫苗中的多糖結合物。更重要的是,它會增強樹突狀細胞的成熟和分化,導致 T H1細胞的活化增強以及細胞毒性 T 淋巴細胞 (CTL) 生成加強,甚至 CD4 T 細胞説明的缺失。甚至有疫苗佐劑的存在也能維持 TLR9 活化作用誘發的 T H1偏移,這些佐劑如:正常促進 T H2偏移的明礬或弗氏不完全佐劑 (IFA)。CpG 寡核苷酸與以下其他佐劑或配方一起製備或聯合給藥時,表現出更強的佐劑活性,如微粒、納米粒子、脂肪乳或類似製劑,當抗原相對較弱時,這些對誘發強反應尤為必要。他們還能加速免疫反應,使抗原劑量減少約兩個數量級,在有些實驗中,對不含CpG 的全劑量疫苗也能產生類似的抗體反應 (Krieg, 2006)。美國 6406705 B1 號專利對 CpG 寡核苷酸、非核酸佐劑和抗原結合使用促使抗原特異性免疫反應進行了描述。一種 CpG TLR9 拮抗劑為 Mologen 公司(德國柏林)的 dSLIM(雙幹環免疫調節劑),這是本發明藥物組合物的優選成分。也可使用其他如 TLR 結合分子,如:RNA 結合 TLR7、TLR8 和/或 TLR9。 CpG immunostimulatory oligonucleotides have been reported to enhance the effect of adjuvants in vaccines. Without being bound by theory, CpG oligonucleotides act by priming the innate (non-adaptive) immune system through Toll-like receptors (TLRs), primarily TLR9. CpG-triggered TLR9 activation enhances antigen-specific humoral and cellular responses to a variety of antigens, including peptide or protein antigens, live or killed viruses, dendritic cell vaccines, autologous cell vaccines, and prophylactic and polysaccharide conjugates in therapeutic vaccines. More importantly, it enhanced dendritic cell maturation and differentiation, resulting in enhanced activation of TH1 cells and enhanced cytotoxic T lymphocyte (CTL) generation, even in the absence of CD4 T cell specification. TLR9 activation-induced TH1 shift was maintained even in the presence of vaccine adjuvants such as alum or incomplete Freund's adjuvant (IFA) that normally promote TH2 shift. CpG oligonucleotides exhibit stronger adjuvant activity when prepared or co-administered with other adjuvants or formulations such as microparticles, nanoparticles, lipid emulsions, or similar formulations that are less effective when the antigen is relatively weak. It is especially necessary to induce a strong response. They also accelerated immune responses, reducing antigen doses by about two orders of magnitude, and in some experiments produced similar antibody responses to full-dose vaccines without CpG (Krieg, 2006). US Patent No. 6,406,705 B1 describes the use of CpG oligonucleotides, non-nucleic acid adjuvants, and antigens in combination to induce antigen-specific immune responses. A CpG TLR9 antagonist is dSLIM (Double Stem Ring Immunomodulator) from Mologen (Berlin, Germany), which is a preferred component of the pharmaceutical composition of the present invention. Other eg TLR binding molecules, eg RNA binding to TLR7, TLR8 and/or TLR9 may also be used.
其他有用的佐劑例子包括(但不限於)化學修飾性 CpG (如 CpR、Idera)、dsRNA 模擬物,如,Poly(I:C) 及其衍生物(如:AmpliGen、Hiltonol、多聚-(ICLC)、多聚 (IC-R)、多聚 (I:C12U))、非 CpG 細菌性 DNA 或 RNA 以及免疫活性小分子和抗體,如:環磷醯胺、舒尼替單抗、貝伐單抗®、西樂葆、NCX-4016、西地那非、他達拉非、伐地那非、索拉非尼、替莫唑胺、temsirolimus、XL-999、CP-547632、帕唑帕尼、VEGF Trap、ZD2171、AZD2171、抗-CTLA4、免疫系統的其他抗體靶向性主要結構(如:抗-CD40、抗-TGFβ、抗-TNFα受體) 和 SC58175,這些藥物都可能有治療作用和/或充當佐劑。技術人員無需過度進行不當實驗就很容易確定本發明中有用的佐劑和添加劑的數量和濃度。Examples of other useful adjuvants include, but are not limited to, chemically modified CpGs (eg, CpR, Idera), dsRNA mimetics, eg, Poly(I:C) and derivatives thereof (eg: AmpliGen, Hiltonol, Poly-( ICLC), poly(IC-R), poly(I:C12U)), non-CpG bacterial DNA or RNA, and immunologically active small molecules and antibodies such as: cyclophosphamide, sunitinib, bevac MAb®, Celebrex, NCX-4016, Sildenafil, Tadalafil, Vardenafil, Sorafenib, Temozolomide, temsirolimus, XL-999, CP-547632, Pazopanib, VEGF Trap , ZD2171, AZD2171, anti-CTLA4, other antibodies targeting major structures of the immune system (eg: anti-CD40, anti-TGFβ, anti-TNFα receptors) and SC58175, all of which may have therapeutic and/or adjuvant. A skilled artisan can readily determine the amounts and concentrations of adjuvants and additives useful in the present invention without undue undue experimentation.
首選佐劑是抗-CD40、咪喹莫特、瑞喹莫德、GM-CSF、環磷醯胺、舒尼替尼、貝伐單抗、干擾素α、CpG 寡核苷酸及衍生物、多聚(I:C)及衍生物、RNA、西地那非和PLG或病毒顆粒的微粒製劑。Preferred adjuvants are anti-CD40, imiquimod, requimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, interferon alpha, CpG oligonucleotides and derivatives, Microparticle formulations of poly(I:C) and derivatives, RNA, sildenafil and PLG or viral particles.
本發明藥物組合物的一個優選實施方案中,佐劑從含集落刺激因數製劑中選擇,如粒細胞巨噬細胞集落刺激因數(GM-CSF,沙格司亭)、環磷醯胺、咪喹莫特、resiquimod 和干擾素-α。In a preferred embodiment of the pharmaceutical composition of the present invention, the adjuvant is selected from preparations containing colony-stimulating factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sagrastim), cyclophosphamide, imiquine Mott, resiquimod and interferon-alpha.
本發明藥物組合物的一個優選實施方案中,佐劑從含集落刺激因數製劑中選擇,如粒細胞巨噬細胞集落刺激因數(GM-CSF,沙格司亭)、環磷醯胺、咪喹莫特和 resimiquimod。在本發明藥物組合物的一個優選實施方案中,佐劑為環磷醯胺、咪喹莫特或 resiquimod。更優選的佐劑是 Montanide IMS 1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA-51、聚-ICLC (Hiltonol®) 和抗CD40 mAB或其組合物。In a preferred embodiment of the pharmaceutical composition of the present invention, the adjuvant is selected from preparations containing colony-stimulating factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sagrastim), cyclophosphamide, imiquine Mott and resimiquimod. In a preferred embodiment of the pharmaceutical composition of the present invention, the adjuvant is cyclophosphamide, imiquimod or resiquimod. More preferred adjuvants are Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, poly-ICLC (Hiltonol®) and anti-CD40 mAB or combinations thereof.
此組合藥物為非腸道注射使用,如皮下、皮內、肌肉注射,也可口服。為此,肽和其他選擇性分子在藥用載體中分解或懸浮,優選為水載體。此外,組合物可包含輔料,如:緩衝劑、結合劑、衝擊劑、稀釋劑、香料、潤滑劑等。這些肽也可與免疫刺激物質合用,如:細胞因數。可用於此類組合物的更多輔料可在從 A. Kibbe 所著的 Handbook of Pharmaceutical Excipients (Kibbe, 2000) 等書中獲知。此組合藥物可用於阻止、預防和/或治療腺瘤或癌性疾病。例如,EP2112253 中有示例製劑。This combination drug is used for parenteral injection, such as subcutaneous, intradermal, intramuscular injection, and can also be taken orally. For this purpose, peptides and other selective molecules are dissolved or suspended in a pharmaceutically acceptable carrier, preferably an aqueous carrier. In addition, the composition may contain adjuvants such as: buffers, binders, shock agents, diluents, fragrances, lubricants, and the like. These peptides can also be used in combination with immunostimulatory substances such as cytokines. Further excipients useful in such compositions are known from A. Kibbe, Handbook of Pharmaceutical Excipients (Kibbe, 2000), among others. This combination drug can be used to stop, prevent and/or treat adenoma or cancerous disease. For example, there are exemplified formulations in EP2112253.
重要的是要認識到,通過本發明的疫苗引發的免疫應答在不同的細胞階段和開發的不同階段攻擊癌症。而且不同的癌症相關信號通路被攻擊。這相對於其他疫苗的優勢,這些疫苗只針對一個或幾個靶標,這可能會導致腫瘤很容易適應於攻擊(腫瘤逃逸)。此外,並非所有的個體腫瘤都表達相同模式的抗原。因此,幾個腫瘤相關肽的組合確保了每個腫瘤都承擔至少一些靶標。該組合物以這樣的方式設計,預期每個腫瘤可表達幾種抗原並覆蓋腫瘤生長和維持所需要的幾種獨立的途徑。因此,疫苗可易於「現成的」用於較大患者群體。這意味著,預選擇接受疫苗治療的患者可限制為 HLA 分型,無需抗原表達的任何額外的生物標誌物評估,但仍然確保多個靶標同時被誘導的免疫應答攻擊,這對於療效很重要 (Banchereau et al., 2001; Walter et al., 2012)。It is important to realize that the immune response elicited by the vaccine of the present invention attacks cancer at different cellular stages and at different stages of development. And different cancer-related signaling pathways were attacked. This is an advantage over other vaccines, which target only one or a few targets, which may cause tumors to readily adapt to attack (tumor escape). Furthermore, not all individual tumors express the same pattern of antigens. Thus, the combination of several tumor-associated peptides ensures that each tumor bears at least some of the targets. The composition is designed in such a way that each tumor is expected to express several antigens and cover several independent pathways required for tumor growth and maintenance. Thus, vaccines can be easily "off the shelf" for larger patient populations. This means that patients preselected for vaccine treatment can be restricted to HLA typing without any additional biomarker assessment of antigen expression, but still ensure that multiple targets are simultaneously attacked by the induced immune response, which is important for efficacy ( Banchereau et al., 2001; Walter et al., 2012).
本文所用的「支架」一詞是指與(如抗原)決定因數特異性結合的分子。在一項實施方案中,支架是能夠引導其所連接的實體(例如,(第二)抗原結合部分) 至目標靶點,例如,至特定類型的腫瘤細胞或承載抗原決定簇的腫瘤基質(如根據目前申請中肽和 MHC 的複合體)。在另一項實施例中,支架能夠通過其靶抗原(例如 T 細胞受體複合體抗原)啟動信號通路。支架包括但不限於抗體及其片段,抗體的抗原結合區,其包含抗體重鏈可變區和抗體輕鏈可變區,結合的蛋白包括至少一個錨蛋白重複序列基元和單域抗原結合 (SDAB) 分子、適體、(可溶)TCR 和(經修飾的)細胞,例如同種異體或自體 T 細胞。為了評估某個分子是否是結合至靶點的支架,可進行結合測定。The term "scaffold" as used herein refers to a molecule that specifically binds (eg, an antigenic) determinant. In one embodiment, the scaffold is capable of directing the entity to which it is attached (eg, a (second) antigen binding moiety) to a target of interest, eg, to a specific type of tumor cell or tumor stroma bearing an antigenic determinant (eg, complexes of peptides and MHC according to the current application). In another embodiment, the scaffold is capable of initiating a signaling pathway through its target antigen (eg, T cell receptor complex antigen). Scaffolds include, but are not limited to, antibodies and fragments thereof, an antigen-binding region of an antibody comprising an antibody heavy chain variable region and an antibody light chain variable region, bound proteins including at least one ankyrin repeat motif and single-domain antigen binding ( SDAB) molecules, aptamers, (soluble) TCRs and (modified) cells such as allogeneic or autologous T cells. To assess whether a molecule is a scaffold for binding to a target, a binding assay can be performed.
「特定」結合系指,與其他天然肽-MHC 複合體相比,該支架與感興趣的肽-MHC複合體更好地結合,結合程度為,擁有能夠殺死承載特定靶點細胞的活性分子的支架不能夠殺死無特定靶點但表現一個或多個其他肽-MHC複合體的另一細胞。如果交叉反應性肽-MHC 的肽並不是天然的,即,並非來自人 HLA-多肽組,則結合至其他肽-MHC 複合體是無關緊要的。評估靶細胞殺傷的測試在本領域中是公知的。它們應該含有未改變的肽-MHC 表現的靶細胞(原發細胞或細胞系)或載有肽的細胞進行,以便達到天然肽-MHC 的水準。"Specific" binding means that the scaffold binds the peptide-MHC complex of interest better than other native peptide-MHC complexes to the extent that it possesses an active molecule capable of killing cells bearing the specific target The scaffolds were not able to kill another cell without a specific target but expressing one or more other peptide-MHC complexes. Binding to other peptide-MHC complexes is irrelevant if the cross-reactive peptide-MHC peptide is not native, ie not from the human HLA-peptidome. Assays to assess target cell killing are well known in the art. They should be performed on target cells (primary cells or cell lines) or peptide-loaded cells containing unchanged peptide-MHC expression in order to achieve the level of native peptide-MHC.
各支架可包括一個標記,其通過確定是否存在或不存在標籤所提供的信號可檢測到結合支架。例如,該支架可用螢光染料或任何其他適用的細胞標記分子進行標記。此類標記分子是本領域中公知的。例如,通過螢光染料進行的螢光標記可通過螢光或鐳射掃描顯微術或流式細胞術提供結合適體的視覺化。Each scaffold can include a label that can detect the bound scaffold by a signal provided by the presence or absence of the label. For example, the scaffold can be labeled with a fluorescent dye or any other suitable cell marker molecule. Such marker molecules are well known in the art. For example, fluorescent labeling by fluorescent dyes can provide visualization of bound aptamers by fluorescent or laser scanning microscopy or flow cytometry.
各支架可與第二個活性分子(例如 IL-21、抗 CD3、抗 CD28)共軛。Each scaffold can be conjugated to a second active molecule (e.g. IL-21, anti-CD3, anti-CD28).
關於多肽支架的進一步資訊,可參閱,例如,在 WO 2014/071978A1 背景技術部分,並作為參考文獻引用。Further information on polypeptide scaffolds can be found, for example, in the background section of WO 2014/071978 A1 and incorporated by reference.
本發明還涉及適體。適體(例如,參見 WO 2014/191359 及其中引用的文獻)是短的單鏈核酸分子,其可以折疊為所定義的三維結構並識別特定的靶標結構。它們似乎是開發靶向治療的合適替代方法。適體已顯示可選擇性與具有高親和力和特異性的複合體靶標相結合。The present invention also relates to aptamers. Aptamers (see, eg, WO 2014/191359 and references cited therein) are short single-stranded nucleic acid molecules that can fold into a defined three-dimensional structure and recognize specific target structures. They appear to be suitable alternatives for developing targeted therapies. Aptamers have been shown to selectively bind complex targets with high affinity and specificity.
識別細胞表面分子的適體在過去十年內已經確定,並為開發診斷和治療方法提供了手段。由於適體已顯示幾乎無毒性和免疫原性,因此,它們是生物醫學應用中有前景的候選物質。事實上適體,例如攝護腺特異性膜抗原識別適體,已被成功地用於靶向治療並在體內模型的異種移植物中顯示出功能。此外,認識到特定腫瘤細胞系的適體也已確定。Aptamers that recognize cell surface molecules have been identified over the past decade and provide the means for developing diagnostics and therapeutics. Aptamers are promising candidates for biomedical applications as they have been shown to be virtually non-toxic and immunogenic. Indeed aptamers, such as prostate-specific membrane antigen-recognizing aptamers, have been successfully used in targeted therapy and have shown function in xenografts in in vivo models. In addition, aptamers to recognize specific tumor cell lines have also been identified.
可選擇 DNA 適體來揭示各種癌細胞的廣譜識別屬性,特別是那些來自於實體瘤的細胞,而非致瘤和主要健康細胞不被識別。如果所識別的適體不僅識別腫瘤特異性子類型,而且與一系列腫瘤相互作用,這使適體適用于作為所謂的廣譜診斷和治療手段。DNA aptamers can be selected to reveal broad-spectrum recognition properties of various cancer cells, especially those derived from solid tumors, while non-tumorigenic and predominantly healthy cells are not recognized. If the identified aptamer not only recognizes tumor-specific subtypes, but also interacts with a range of tumors, this makes the aptamer suitable as a so-called broad-spectrum diagnostic and therapeutic tool.
此外,用流式細胞儀對細胞結合行為的研究顯示,適體在納摩爾範圍內顯示出很好的親和力。Furthermore, cell-binding behavior studies using flow cytometry revealed that the aptamers displayed good affinities in the nanomolar range.
適體用於診斷和治療目的。此外,也可能顯示,一些適體被腫瘤細胞吸取,因而可作為抗癌劑靶向遞送的分子賦形劑,例如 siRNA 進入腫瘤細胞。Aptamers are used for diagnostic and therapeutic purposes. In addition, it may also be shown that some aptamers are taken up by tumor cells and thus serve as molecular excipients for the targeted delivery of anticancer agents, such as siRNA, into tumor cells.
可選擇適體針對複合體的靶標,如細胞和組織以及包含、優選包括根據任何 SEQ ID NO 1 至 SEQ ID NO 161 的一個序列、根據當前發明的肽複合體與 MHC 分子,使用細胞 SELEX(通過指數富集的配體系統進化)技術。Aptamers can be selected for complex targets such as cells and tissues and peptide complexes and MHC molecules comprising, preferably comprising, a sequence according to any of
本發明中的肽可用于生成和開發出針對 MHC/肽複合物的特定抗體。這些抗體可用於治療,將毒素或放射性物質靶向病變組織。這些抗體的另一用途是為了成像之目的(如 PET)將放射性核素靶向病變組織。這可有助於檢測小轉移灶或確定病變組織的大小和準確位置。The peptides of the present invention can be used to generate and develop specific antibodies against MHC/peptide complexes. These antibodies can be used in therapy, targeting toxins or radioactive substances to diseased tissue. Another use of these antibodies is to target radionuclides to diseased tissue for imaging purposes such as PET. This can help detect small metastases or determine the size and exact location of diseased tissue.
因此,本發明的另一方面是提出產生特異性結合至與 HLA 限制性抗原絡合的 I 或 II 類人主要組織相容性複合體 (MHC) 的一種重組抗體的方法,該方法包括:用可溶形式的與 HLA 限制性抗原絡合的 (MHC) I 或 II 類分子對包含表達所述主要組織相容性說複合體 (MHC) I 或 II 類的基因工程非人哺乳動物進行免疫;將 mRNA 分子與產生所述非人哺乳動物細胞的抗體分離;產生一個噬菌體顯示庫,顯示由所述 mRNA 分子編碼的蛋白分子;以及將至少一個噬菌體與所述噬菌體顯示庫分離,所述的至少一個噬菌體顯示所述抗體特異性地結合至與 HLA 限制性抗原絡合的所述人主要組織相容性說複合體 (MHC) I 或 II 類。Therefore, another aspect of the present invention is to propose a method of producing a recombinant antibody that specifically binds to a human major histocompatibility complex (MHC) class I or II complexed with an HLA-restricted antigen, the method comprising: using immunizing a genetically engineered non-human mammal comprising expressing said major histocompatibility complex (MHC) class I or II of a soluble form of a (MHC) class I or II molecule complexed with an HLA-restricted antigen; isolating mRNA molecules from antibodies that produce said non-human mammalian cells; generating a phage display library displaying protein molecules encoded by said mRNA molecules; and isolating at least one phage from said phage display library, said at least one phage display library One phage showed that the antibody specifically bound to the human major histocompatibility complex (MHC) class I or II complexed with HLA-restricted antigens.
本發明的另一方面提出一種抗體,其特異性結合至與一種 HLA 限制性抗原絡合的 I 或 II 類人主要組織相容性說複合體 (MHC),其中該抗體優選為多克隆抗體、單克隆抗體、雙特異性抗體和/或嵌合抗體。Another aspect of the present invention provides an antibody that specifically binds to a human major histocompatibility complex (MHC) of class I or II complexed with an HLA-restricted antigen, wherein the antibody is preferably a polyclonal antibody, Monoclonal, bispecific and/or chimeric antibodies.
產生這種抗體和單鏈 I 類主要組織相容性複合物的相應方法,以及產生這些抗體的其他工具在 WO 03/068201、WO 2004/084798、WO 01/72768、WO 03/070752 以及出版物 (Cohen et al., 2003a; Cohen et al., 2003b; Denkberg et al., 2003) 中進行了披露,為了本發明之目的,所有參考文獻通過引用被完整地併入本文。Corresponding methods for producing such antibodies and single-chain class I major histocompatibility complexes, as well as other tools for producing these antibodies, are described in WO 03/068201, WO 2004/084798, WO 01/72768, WO 03/070752 and publications (Cohen et al., 2003a; Cohen et al., 2003b; Denkberg et al., 2003), all of which are hereby incorporated by reference in their entirety for the purposes of the present invention.
優選地,該抗體與複合體的結合親和力低於 20 納摩爾,優選為低於 10 納摩爾,這在本發明情況下也被視為具有「特異性」。Preferably, the binding affinity of the antibody to the complex is below 20 nanomolar, preferably below 10 nanomolar, which is also considered "specific" in the context of the present invention.
本發明涉及一種肽,包含選自 SEQ ID NO:1 至 SEQ ID NO:161組成的組的一個序列或該序列的與 SEQ ID NO:1 至 SEQ ID NO:161 具有 88% 同源性(優選為相同)的一種變體,或誘導與所述變異肽發生 T 細胞交叉反應的一種變體,其中,所述肽不是基本的全長多肽。The present invention relates to a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 161 or a sequence having 88% homology to SEQ ID NO: 1 to SEQ ID NO: 161 (preferably is the same), or a variant that induces T-cell cross-reactivity with the variant peptide, wherein the peptide is not an essential full-length polypeptide.
本發明進一步涉及一種肽,包含選自 SEQ ID NO:1 至 SEQ ID NO:161 組成的組的一個序列、或與 SEQ ID NO:1 至 SEQ ID NO:161 具有至少 88% 同源性(優選為相同)的一種變體,其中所述肽或變體的總長度為 8 至 100 個、優選為 8 至 30 個、最優選為 8 至 14 個氨基酸。The present invention further relates to a peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 161, or having at least 88% homology (preferably with SEQ ID NO: 1 to SEQ ID NO: 161) is the same), wherein the peptide or variant has a total length of 8 to 100, preferably 8 to 30, most preferably 8 to 14 amino acids in length.
本發明進一步涉及本發明的肽,其具有與主要組織相容性複合體 (MHC) I 或 II 類分子結合的能力。The present invention further relates to the peptides of the present invention, which have the ability to bind to major histocompatibility complex (MHC) class I or II molecules.
本發明進一步涉及本發明中的肽,其中肽系由或基本系由根據 SEQ ID NO:1 至 SEQ ID NO:161 的一個氨基酸序列組成。The present invention further relates to the peptide of the present invention, wherein the peptide consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 161.
本發明進一步涉及本發明的肽,其中該肽(在化學上)被修飾和/或包含非肽鍵。The invention further relates to the peptides of the invention, wherein the peptides are (chemically) modified and/or comprise non-peptide bonds.
本發明進一步涉及本發明的肽,其中該肽為融合蛋白的一部分,特別包括 HLA-DR 抗原相關不變鏈 (Ii ) 的 N-端氨基酸,或其中該肽與一種抗體(例如,樹突狀細胞特定抗體)融合。The present invention further relates to a peptide of the present invention, wherein the peptide is part of a fusion protein, in particular comprising the N-terminal amino acid of the HLA-DR antigen-associated invariant chain (Ii), or wherein the peptide is combined with an antibody (eg, dendritic cell-specific antibody) fusion.
本發明進一步涉及一種核酸,其編碼本發明所述肽,前提是該肽並非完整(完全)的人蛋白。The invention further relates to a nucleic acid encoding the peptide of the invention, provided that the peptide is not a complete (complete) human protein.
本發明進一步涉及一種本發明的核酸,為 DNA、cDNA、PNA、RNA,也可能為其組合物。The present invention further relates to a nucleic acid of the present invention, which is DNA, cDNA, PNA, RNA, and possibly a combination thereof.
本發明進一步涉及一種能表達本發明核酸的表達載體。The present invention further relates to an expression vector capable of expressing the nucleic acid of the present invention.
本發明進一步涉及本發明的一種肽、本發明的一種核酸或本發明的一種藥用表達載體,特別是用於治療胰腺癌。The present invention further relates to a peptide of the present invention, a nucleic acid of the present invention or a pharmaceutical expression vector of the present invention, in particular for the treatment of pancreatic cancer.
本發明進一步涉及含本發明核酸或本發明表達載體的一種宿主細胞。The invention further relates to a host cell containing the nucleic acid of the invention or the expression vector of the invention.
本發明進一步涉及本發明的宿主細胞,其為抗原表現細胞,優選為樹突細胞。The present invention further relates to the host cell of the present invention, which is an antigen-expressing cell, preferably a dendritic cell.
本發明進一步涉及配製本發明一種肽的一種方法,所述方法包括培養本發明的宿主細胞和從所述宿主細胞或其培養基中分離肽。The present invention further relates to a method of formulating a peptide of the present invention, the method comprising culturing a host cell of the present invention and isolating the peptide from the host cell or the culture medium thereof.
本發明進一步涉及本發明中的方法,其中抗原通過與足夠量的含抗原提成細胞的抗原結合被載入表達於合適抗原表現細胞表面的 I 或 II 類 MHC 分子。The present invention further relates to the method of the present invention, wherein the antigen is loaded into MHC class I or II molecules expressed on the surface of suitable antigen-expressing cells by binding to a sufficient amount of antigen containing antigen-presenting cells.
本發明進一步涉及本發明的方法,其中該抗原表現細胞包括一個表達載體,該載體有能力表達含 SEQ ID NO:1 至 SEQ ID NO:161 的肽或所述變體氨基酸序列。The present invention further relates to the method of the present invention, wherein the antigen-expressing cell comprises an expression vector capable of expressing a peptide comprising SEQ ID NO: 1 to SEQ ID NO: 161 or said variant amino acid sequence.
本發明進一步涉及以本發明方法製造的啟動 T 細胞,其中所述 T 細胞有選擇性地識別一種細胞,該細胞異常表達含一種本發明氨基酸序列的多肽。The present invention further relates to prime T cells produced by the method of the present invention, wherein said T cells selectively recognize a cell that abnormally expresses a polypeptide comprising an amino acid sequence of the present invention.
本發明進一步涉及一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明任何氨基酸序列的多肽,該方法包括給予患者本發明的有效量 T 細胞。The present invention further relates to a method of killing target cells of a patient, wherein the target cells of the patient abnormally express a polypeptide comprising any of the amino acid sequences of the present invention, the method comprising administering to the patient an effective amount of T cells of the present invention.
本發明進一步涉及任何所述肽、本發明的一種核酸、本發明的一種表達載體、本發明的一種細胞、本發明一種作為藥劑或製造藥劑的啟動細胞毒性 T 淋巴細胞的用途。本發明進一步涉及一種本發明的用途,其中藥劑可有效抗癌。The present invention further relates to the use of any of said peptides, a nucleic acid of the present invention, an expression vector of the present invention, a cell of the present invention, a cell of the present invention as a medicament or to manufacture a medicament to prime cytotoxic T lymphocytes. The present invention further relates to a use of the present invention wherein the medicament is effective against cancer.
本發明進一步涉及一種本發明的用途,其中該藥劑為一種疫苗。本發明進一步涉及一種本發明的用途,其中藥劑可有效抗癌。The present invention further relates to a use of the present invention, wherein the medicament is a vaccine. The present invention further relates to a use of the present invention wherein the medicament is effective against cancer.
本發明還一般涉及本發明的用途,其中所述癌細胞為胰腺癌細胞或其他實體或血液腫瘤細胞,如:肺癌、腎癌、腦癌、胃癌、結腸或直腸癌、肝癌、攝護腺癌、白血病、乳腺癌、梅克爾細胞癌 (MCC)、黑色素瘤、卵巢癌、食管癌、膀胱癌、子宮內膜癌、膽囊癌和膽管癌。The present invention also generally relates to the use of the present invention, wherein the cancer cells are pancreatic cancer cells or other solid or hematological tumor cells, such as: lung cancer, kidney cancer, brain cancer, gastric cancer, colon or rectal cancer, liver cancer, prostate cancer , leukemia, breast cancer, Merkel cell carcinoma (MCC), melanoma, ovarian cancer, esophageal cancer, bladder cancer, endometrial cancer, gallbladder cancer and bile duct cancer.
本發明進一步涉及一種基於本發明肽的特定標誌物蛋白和生物標誌物,在此成為「靶標」,其可用於診斷和/或判斷胰腺癌的預後。本發明還涉及這些供癌症治療使用的新靶點。The present invention further relates to specific marker proteins and biomarkers based on the peptides of the present invention, herein referred to as "targets", which can be used to diagnose and/or determine the prognosis of pancreatic cancer. The present invention also relates to these novel targets for use in cancer therapy.
本文中術語「抗體」為廣義上的定義,既包括多克隆也包括單克隆抗體。除了完整或「全部」的免疫球蛋白分子,「抗體」這一術語還包括這些免疫球蛋白分子和人源化免疫球蛋白分子的片段(如,CDR、Fv、Fab 和 Fc 片段)或聚合物,只要它們表現出本發明的任何期望屬性(例如,胰腺癌標誌物(多)肽的特異性結合、將毒素傳遞給癌症標誌物基因表達水準增加時的胰腺癌細胞和/或抑制胰腺癌標誌物多肽的活性)。The term "antibody" herein is broadly defined to include both polyclonal and monoclonal antibodies. In addition to intact or "whole" immunoglobulin molecules, the term "antibody" also includes fragments (eg, CDR, Fv, Fab, and Fc fragments) or polymers of these and humanized immunoglobulin molecules as long as they exhibit any of the desired properties of the invention (eg, specific binding of pancreatic cancer marker (poly)peptides, delivery of toxins to pancreatic cancer cells at increased levels of cancer marker gene expression and/or inhibition of pancreatic cancer markers activity of the peptide).
只要有可能,本發明的抗體可從商業來源購買。本發明的抗體也可能使用已知的方法制得。技術人員會瞭解全長胰腺癌標誌物多肽或其片段可用于製備本發明的抗體。用於產生本發明抗體的多肽可部分或全部地由天然源經純化而得,也可利用重組 DNA 技術生產。Wherever possible, antibodies of the invention can be purchased from commercial sources. Antibodies of the present invention may also be prepared using known methods. The skilled artisan will appreciate that full length pancreatic cancer marker polypeptides or fragments thereof can be used to prepare the antibodies of the invention. The polypeptides used to generate the antibodies of the present invention can be purified in part or in whole from natural sources, or can be produced using recombinant DNA technology.
例如,本發明的編碼肽的 cDNA,例如,該肽為根據 SEQ ID NO:1 至 SEQ ID NO:161 多肽的肽,或其中一個變體或片段,可在原核細胞中(如:細菌)或真核細胞(如:酵母、昆蟲或哺乳動物細胞)中表達,之後,可純化重組蛋白,並用於產生一種特異性結合用於產生本發明抗體的胰腺癌標誌物多肽的單克隆或多克隆抗體製劑。For example, a cDNA of the invention encoding a peptide, eg, a peptide according to a polypeptide of SEQ ID NO: 1 to SEQ ID NO: 161, or a variant or fragment thereof, may be present in prokaryotic cells (eg, bacteria) or Expression in eukaryotic cells (eg, yeast, insect or mammalian cells), after which the recombinant protein can be purified and used to generate a monoclonal or polyclonal antibody that specifically binds to the pancreatic cancer marker polypeptide used to generate the antibody of the invention preparation.
本領域的技術人員會認識到,兩種或兩種以上不同集合的單克隆抗體或多克隆抗體能最大限度地增加獲得一種含預期用途所需的特異性和親和力(例如,ELISA 法、免疫組織化學、體內成像、免疫毒素療法)的抗體的可能性。根據抗體的用途,用已知的方法對其期望活性進行測試(例如,ELISA 法、免疫組織化學、免疫治療等;要獲取產生和測試抗體的進一步指導,請參閱,例如,Greenfield, 2014 (Greenfield, 2014))。例如,該抗體可用 ELISA 法或免疫印跡法、免疫組織化學染色福馬林固定的癌組織或冰凍的組織切片進行檢測。在初次體外表徵後,用於治療或體內診斷用途的抗體根據已知的臨床測試方法進行檢測。Those skilled in the art will recognize that two or more distinct sets of monoclonal or polyclonal antibodies maximize the specificity and affinity required for an intended use (eg, ELISA, immunohistochemical chemistry, in vivo imaging, immunotoxin therapy) the possibility of antibodies. Depending on the application of the antibody, test it for desired activity by known methods (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on generating and testing antibodies, see, e.g., Greenfield, 2014 (Greenfield, 2014). , 2014)). For example, the antibody can be detected by ELISA or immunoblotting, immunohistochemical staining of formalin-fixed cancer tissue, or frozen tissue sections. Following initial in vitro characterization, antibodies for therapeutic or in vivo diagnostic use are tested according to known clinical testing methods.
此處使用的術語「單克隆抗體」系指從大量同質抗體中獲得的一種抗體,即,由相同的抗體組成的抗體群,但可能少量表現的自然突變除外。此處所述的單克隆抗體具體包括「嵌合」抗體,其中一部分重鏈和/或輕鏈與從特定物種中獲得的抗體或屬於特定抗體類型和分類型抗體的相應序列相同(同質),同時,剩餘鏈與從其他物種中獲得的抗體或屬於特定抗體類型和子類型抗體的相應序列以及這些抗體的片段相同(同質),只要他們表現出預期的拮抗活性(美國 4816567 號專利,其在此以其整體併入)。As used herein, the term "monoclonal antibody" refers to an antibody obtained from a large number of homogeneous antibodies, ie, a population of antibodies composed of identical antibodies, except for natural mutations that may manifest in small amounts. Monoclonal antibodies as described herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chains are identical (homogeneous) to the corresponding sequences of antibodies obtained from a particular species or belonging to a particular antibody class and class, At the same time, the remaining chains are identical (homogeneous) to the corresponding sequences of antibodies obtained from other species or of antibodies belonging to specific antibody classes and subclasses, and fragments of these antibodies, provided they exhibit the expected antagonistic activity (US Pat. No. 4,816,567, incorporated herein by reference). incorporated in its entirety).
本發明的單克隆抗體可能使用雜交瘤方法制得。在雜交瘤方法中,老鼠或其他適當的宿主動物,通常用免疫製劑以引發產生或能產生將特異性結合至免疫製劑的抗體。或者,淋巴細胞可在體外進行免疫。The monoclonal antibodies of the present invention may be prepared using the hybridoma method. In the hybridoma method, a mouse or other suitable host animal is typically immunized with an immunization agent to elicit the production or production of antibodies that will specifically bind to the immunization agent. Alternatively, lymphocytes can be immunized in vitro.
單克隆抗體也可由 DNA 重組方法制得,如:美國 4816567 號專利所述。編碼本發明單克隆抗體的 DNA 可很容易地使用傳統程序進行分離和測序(例如:通過使用能與編碼鼠抗體重鏈和輕鏈的基因特異性結合的寡核苷酸探針)。Monoclonal antibodies can also be made by recombinant DNA methods, as described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (eg, by using oligonucleotide probes that bind specifically to genes encoding murine antibody heavy and light chains).
體外方法也適用於製備單價抗體。抗體消化以產生抗體的片段,尤其是 Fab 片段,可以通過使用本領域已知的常規技術完成。例如,可以通過使用木瓜蛋白酶完成消化。木瓜蛋白酶消化的實施例在 WO 94/29348和美國 4342566 號專利中有描述。抗體的木瓜蛋白酶消化通常產生兩種相同的抗原結合性片段,稱為 Fab 片段(每個片段都有一個抗原結合點)和殘餘 Fc 片段。胃蛋白酶處理產生一個 F(ab') 2片段和一個 pFc' 片段。 In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments of antibodies, particularly Fab fragments, can be accomplished using conventional techniques known in the art. For example, digestion can be accomplished by using papain. Examples of papain digestion are described in WO 94/29348 and US Pat. No. 4,342,566. Papain digestion of antibodies typically produces two identical antigen-binding fragments, called Fab fragments (each with an antigen-binding site) and residual Fc fragments. Pepsin treatment produces an F(ab') 2 fragment and a pFc' fragment.
抗體片段,不論其是否附著於其他序列,均可包括特定區域或特定氨基酸殘基的插入、刪除、替換、或其他選擇性修飾,但前提是,片段的活性與非修飾的抗體或抗體片段相比沒有顯著的改變或損害。這些修飾可提供一些額外的屬性,如:刪除/添加可與二硫鍵結合的氨基酸,以增加其生物壽命、改變其分泌特性等。在任何情況下,抗體片段必須擁有生物活性的特性,如:結合活性、調節結合域的結合力等。抗體的功能性或活性區域可通過蛋白特定區域的基因突變、隨後表達和測試所表達的多肽進行確定。這些方法為本行業技術人員所熟知,可包括編碼抗體片段的核酸的特定位點基因突變。Antibody fragments, whether or not they are attached to other sequences, may include insertions, deletions, substitutions, or other selective modifications of specific regions or specific amino acid residues, provided that the activity of the fragment is comparable to that of the unmodified antibody or antibody fragment. than no significant change or damage. These modifications can provide some additional properties, such as: deletion/addition of amino acids that can bind disulfide bonds to increase their biological lifespan, alter their secretory properties, etc. In any case, the antibody fragment must possess biologically active properties, such as: binding activity, modulation of binding of the binding domain, etc. The functional or active region of an antibody can be determined by genetic mutation of specific regions of the protein, followed by expression and testing of the expressed polypeptide. These methods are well known to those skilled in the art and may involve site-specific genetic mutation of the nucleic acid encoding the antibody fragment.
本發明的抗體可進一步包括人源化抗體或人抗體。非人(如:鼠)抗體的人源化形式為嵌合抗體免疫球蛋白、免疫球蛋白鏈或其片段(如:Fv、Fab、Fab' 或抗體的其他抗原結合序列),其中包含從非人免疫球蛋白中獲得的最小序列。人源化抗體包括人免疫球蛋白(受體抗體),其中來自受體互補決定區 (CDR) 的殘基被來自非人物種(供體抗體)(如具有與其特異性、親和力和能力的小鼠、大鼠或兔子)CDR 的殘基取代。在某些情況下,人類免疫球蛋白的 Fv 框架 (FR) 殘基被相應的非人殘基取代。人源化抗體可能還包括既非受體抗體、也非輸入 CDR 或框架序列中發現的殘基。一般來說,人源化抗體將包括幾乎所有的至少一個、通常為二個可變域,其中,全部或幾乎全部的 CDR 區域均對應於非人免疫球蛋白的區域並且全部或幾乎全部的 FR區域均為人免疫球蛋白相同序列的區域。理想情況是,人源化抗體還將包括至少免疫球蛋白恒定區 (Fc) 的一部分,通常是人免疫球蛋白的恒定區的一部分。The antibodies of the present invention may further include humanized antibodies or human antibodies. Humanized forms of non-human (e.g. murine) antibodies are chimeric antibody immunoglobulins, immunoglobulin chains or fragments thereof (e.g. Fv, Fab, Fab' or other antigen-binding sequences of antibodies) containing Minimal sequence obtained in human immunoglobulin. Humanized antibodies include human immunoglobulins (acceptor antibodies) in which residues from the acceptor complementarity determining regions (CDRs) are replaced by those derived from a non-human species (donor antibodies) such as small proteins with specificity, affinity, and capacity for them. mouse, rat, or rabbit) CDR residue substitutions. In certain instances, Fv framework (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also include residues found in neither the acceptor antibody nor the import CDR or framework sequences. In general, a humanized antibody will include substantially all of at least one, and usually two, variable domains, wherein all or nearly all of the CDR regions correspond to regions of the non-human immunoglobulin and all or nearly all of the FRs The regions are all regions of the same sequence of human immunoglobulins. Ideally, the humanized antibody will also include at least a portion of the constant region (Fc) of an immunoglobulin, typically that of a human immunoglobulin.
人源化非人抗體的方法為本行業所熟知。一般來說,人源化抗體具有一個或多個從非人源頭引入的氨基酸殘基。這些非人氨基酸殘基往往被稱為「輸入」殘基,通常從「輸入」可變域中獲得。人源化基本上可以通過將齧齒動物 CDR 或 CDR 序列取代為相應的人抗體序列而完成。因此,這種「人源化」抗體為嵌合抗體(美國 4816567 號專利),其中大大少於完整的人可變域被來自於非人物種的相應序列取代。在實踐中,人源化抗體通常為人抗體,其中有些 CDR 殘基以及可能的一些 FR 殘基被來自齧齒動物抗體中的類似位點的殘基取代。Methods of humanizing non-human antibodies are well known in the industry. Generally, humanized antibodies have one or more amino acid residues introduced from a non-human source. These non-human amino acid residues are often referred to as "import" residues and are usually obtained from an "import" variable domain. Humanization can essentially be accomplished by substituting rodent CDRs or CDR sequences with the corresponding human antibody sequences. Thus, such "humanized" antibodies are chimeric antibodies (US Pat. No. 4,816,567) in which substantially less than the entire human variable domain has been replaced with corresponding sequences from a non-human species. In practice, humanized antibodies are usually human antibodies in which some CDR residues and possibly some FR residues are replaced by residues from analogous sites in rodent antibodies.
可使用免疫後在內源性免疫球蛋白產生缺失時能產生完整人抗體的轉基因動物(如:小鼠)。例如,它被描述為,嵌合和種系突變小鼠中的抗體重鏈連接區域基因的純合性缺失導致內源性抗體生成的完全抑制。在此種系變種小鼠中人種系免疫球蛋白基因陣列的轉移在抗原挑戰後將導致人抗體的生成。人抗體也可在噬菌體展示庫中產生。Transgenic animals (eg, mice) that produce fully human antibodies after immunization in the absence of endogenous immunoglobulin production can be used. For example, it has been described that homozygous deletion of the antibody heavy chain linker region gene in chimeric and germline mutant mice results in complete inhibition of endogenous antibody production. Transfer of human germline immunoglobulin gene arrays in this strain variant mouse will result in the production of human antibodies following antigen challenge. Human antibodies can also be produced in phage display libraries.
本發明的抗體優選為通過藥用載體的形式給予受試者。通常,在製劑中使用適量的藥用鹽,以使製劑等滲。藥用載體的例子包括生理鹽水、林格氏液和葡萄糖溶液。溶液的 pH 值優選為約 5 至8,更優選為約 7 至7.5。此外,載體還包括緩釋製劑,如:含有抗體的固體疏水性聚合物半透性基質,其中基質為有形物品形式,如:薄膜、脂質體或微粒。本行業的技術人員熟知,某些載體可能為更優選,取決於例如,抗體的給藥途徑和濃度。The antibodies of the present invention are preferably administered to a subject in the form of a pharmaceutically acceptable carrier. Typically, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic. Examples of pharmaceutical carriers include physiological saline, Ringer's solution and dextrose solution. The pH of the solution is preferably about 5 to 8, more preferably about 7 to 7.5. In addition, carriers also include sustained release formulations such as solid hydrophobic polymer semipermeable matrices containing the antibody, wherein the matrices are in the form of tangible objects such as films, liposomes or microparticles. It is well known to those skilled in the art that certain carriers may be more preferred, depending, for example, on the route of administration and concentration of the antibody.
該抗體可通過注射(如:靜脈內、腹腔內、皮下、肌肉內)或通過輸注等其他方法給予受試者、患者或細胞,確保其以有效的形式傳輸到血液中。這些抗體也可以通過瘤內或瘤周途徑給予,從而發揮局部和全身的治療作用。局部或靜脈注射為優選。The antibody can be administered to a subject, patient or cell by injection (eg, intravenous, intraperitoneal, subcutaneous, intramuscular) or by other methods such as infusion, ensuring that it is delivered to the bloodstream in an effective form. These antibodies can also be administered by intratumoral or peritumoral routes, thereby exerting local and systemic therapeutic effects. Topical or intravenous injection is preferred.
抗體給藥的有效劑量和時間表可根據經驗確定,並且作出此類決定屬本行業的技術範圍內。本行業的技術人員會明白,必須給予的抗體劑量根據以下因素會有所不同,例如:接受抗體的受試者、給藥途徑、使用的抗體以及其他正在使用的藥物的特定類型。單獨使用的抗體的通常日劑量可能為約 1 µg/kg 至最多 100 mg/kg 體重或更多,這取決於上述因素。給予抗體,優選為治療胰腺癌後,治療抗體的療效可通過技術人員熟知的不同方法評估。例如:接受治療的受試者癌症的大小、數量和/或分佈可使用標準腫瘤成像技術進行監測。因治療而給予的抗體與不給予抗體時的病程相比,可阻止腫瘤生長、導致腫瘤縮小、和/或阻止新腫瘤的發展,這樣的抗體是一種有效治療癌症的抗體。Effective doses and schedules of antibody administration can be determined empirically, and making such determinations is within the skill of the art. Those skilled in the art will appreciate that the dose of antibody that must be administered will vary depending on factors such as the subject receiving the antibody, the route of administration, the antibody being used, and the particular type of other drug being used. Typical daily doses of antibodies used alone may range from about 1 µg/kg to up to 100 mg/kg of body weight or more, depending on the factors mentioned above. Following administration of the antibody, preferably for the treatment of pancreatic cancer, the efficacy of the therapeutic antibody can be assessed by various methods well known to the skilled artisan. For example, the size, number and/or distribution of cancer in a subject receiving treatment can be monitored using standard tumor imaging techniques. Antibodies that are administered as a result of the therapy that prevent tumor growth, cause tumor shrinkage, and/or prevent the development of new tumors compared to the course of disease when the antibody is not administered are effective in the treatment of cancer.
本發明的另一方面提出了製備識別特異性肽-MHC複合物的可溶性 T 細胞受體 (sTCR) 的一種方法。這種可溶性 T 細胞受體可從特異性 T 細胞克隆中產生,並且它們的親和力可以通過互補決定區靶向誘變而增加。為了 T 細胞受體選擇之目的,可以使用噬菌體展示(美國2010/0113300, (Liddy et al., 2012))。為了在噬菌體展示期間以及實際使用為藥物時穩定 T 細胞受體之目的,可通過非天然二硫鍵、其他共價鍵(單鏈 T 細胞受體)或通過二聚化結構域連接 α 和 β 鏈 (Boulter et al., 2003; Card et al., 2004; Willcox et al., 1999)。T 細胞受體可以連接到毒素、藥物、細胞因數(參見US 2013/0115191)、域招募效應細胞,如抗 CD3 域等,以便對靶細胞執行特定的功能。此外,它可能表達於用於過繼轉移的 T 細胞。進一步的資訊可在 WO 2004/033685A1 和 WO 2004/074322A1 中找到。 sTCR 的組合在 WO 2012/056407A1 中進行了描述。WO 2013/057586A1 中公開了製備的進一步的方法。Another aspect of the present invention proposes a method of making soluble T cell receptors (sTCRs) that recognize specific peptide-MHC complexes. Such soluble T-cell receptors can be generated from specific T-cell clones, and their affinity can be increased by targeted mutagenesis of complementarity-determining regions. For the purpose of T cell receptor selection, phage display can be used (US 2010/0113300, (Liddy et al., 2012)). For the purpose of stabilizing the T cell receptor during phage display and in actual use as a drug, alpha and beta can be linked via non-natural disulfide bonds, other covalent bonds (single-chain T cell receptors), or via dimerization domains chain (Boulter et al., 2003; Card et al., 2004; Willcox et al., 1999). T cell receptors can be linked to toxins, drugs, cytokines (see US 2013/0115191), domains that recruit effector cells, such as anti-CD3 domains, etc., to perform specific functions on target cells. Furthermore, it may be expressed in T cells used for adoptive transfer. Further information can be found in WO 2004/033685A1 and WO 2004/074322A1. The combination of sTCRs is described in WO 2012/056407A1. Further methods of preparation are disclosed in WO 2013/057586A1.
此外,可用本發明的肽和/或 TCR 或抗體或其他結合分子在活檢樣本的基礎上驗證病理師對癌症的診斷。In addition, the peptides and/or TCRs or antibodies or other binding molecules of the invention can be used to validate a pathologist's diagnosis of cancer on the basis of biopsy samples.
該抗體或 TCR 也可用於體內診斷實驗。一般來說,抗體用放射性核素標記(如: 111In、 99Tc、 14C、 131I、 3H、 32P 或 35S),從而可免疫閃爍掃描法使腫瘤局限化。在一實施方案中,其中的抗體或片段與兩個或兩個以上選自包括上述蛋白的組的蛋白質靶標的細胞外域結合,並且親和力值 (Kd) 低於 1 x 10µM。 The antibody or TCR can also be used in in vivo diagnostic experiments. Typically, antibodies are labeled with radionuclides (eg, 111 In, 99 Tc, 14 C, 131 I, 3 H, 32 P, or 35 S) to allow localization of tumors by immunoscintigraphy. In one embodiment, wherein the antibody or fragment binds to the extracellular domain of two or more protein targets selected from the group comprising the above proteins, and has an affinity value (Kd) of less than 1 x 10 µM.
診斷用抗體可通過各種影像學方法使用適合檢測的探針進行標記。探針檢測方法包括但不限於,螢光、光、共聚焦和電鏡方法;磁共振成像和光譜學技術;透視、電腦斷層掃描和正電子發射斷層掃描。合適的探針包括但不限於,螢光素、羅丹明、曙紅及其它螢光團、放射性同位素、黃金、釓和其他稀土、順磁鐵、氟-18 和其他正電子發射放射性核素。此外,探針可能是雙功能或多功能的,並且用一種以上的上述方法可進行檢測。這些抗體可用所述的探針直接或間接進行標記。抗體探針的連接,包括探針的共價連接、將探針融合入抗體、以及螯合化合物的共價連接從而結合探針、以及其他本行業熟知的方法。對於免疫組織化學方法,疾病組織樣本可能是新鮮或冷凍或可能包埋於石蠟中以及用福馬林等防腐劑固定。固定或包埋的切片包括與標記一抗和二抗接觸的樣本,其中該抗體用於檢測原位 蛋白的表達。Diagnostic antibodies can be labeled with probes suitable for detection by various imaging methods. Probe detection methods include, but are not limited to, fluorescence, light, confocal and electron microscopy methods; magnetic resonance imaging and spectroscopy techniques; fluoroscopy, computed tomography, and positron emission tomography. Suitable probes include, but are not limited to, luciferin, rhodamine, eosin and other fluorophores, radioisotopes, gold, gadolinium and other rare earths, paramagnets, fluorine-18 and other positron emitting radionuclides. In addition, probes may be bifunctional or multifunctional and detectable using more than one of the above methods. These antibodies can be labeled directly or indirectly with the probes described. Attachment of antibody probes includes covalent attachment of probes, fusion of probes into antibodies, and covalent attachment of chelating compounds to bind probes, as well as other methods well known in the art. For immunohistochemical methods, disease tissue samples may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin. Fixed or embedded sections include samples contacted with labeled primary and secondary antibodies used to detect protein expression in situ.
本發明的另一方面包括一種體外製備啟動的 T 細胞的方法,該方法包括將 T 細胞與載有抗原的人 MHC 分子進行體外接觸,這些分子在合適的抗原表現細胞表面表達足夠的一段時間從而以抗原特異性方式啟動 T 細胞,其中所述抗原為根據本發明所述的一種肽。優選情況是足夠量的抗原與抗原表現細胞一同使用。Another aspect of the invention includes a method of producing primed T cells in vitro, the method comprising in vitro contacting T cells with antigen-loaded human MHC molecules that are expressed on the surface of suitable antigen-expressing cells for a period of time sufficient to allow T cells are primed in an antigen-specific manner, wherein the antigen is a peptide according to the present invention. Preferably, a sufficient amount of antigen is used with the antigen-expressing cells.
優選情況是,哺乳動物細胞的TAP 肽轉運載體缺乏或水準下降或功能降低。缺乏 TAP 肽轉運載體的適合細胞包括 T2、RMA-S 和果蠅細胞。TAP 是與抗原加工相關的轉運載體。Preferably, the TAP peptide transporter in mammalian cells is deficient or reduced in level or function. Suitable cells that lack the TAP peptide transporter include T2, RMA-S, and Drosophila cells. TAP is a transporter associated with antigen processing.
人體肽載入的缺陷細胞株 T2 從屬美國菌種保藏中心(ATCC, 12301 Parklawn Drive, Rockville, Maryland 20852,美國)目錄號 CRL1992;果蠅細胞株 Schneider 2 號株從屬 ATCC 目錄 CRL 19863;小鼠 RMA-S 細胞株 Ljunggren 等人描述過 (Ljunggren and Karre, 1985)。Human peptide loading deficient cell line T2 is under the American Type Culture Collection (ATCC, 12301 Parklawn Drive, Rockville, Maryland 20852, USA) catalog number CRL1992; Drosophila cell line Schneider 2 is under ATCC catalog CRL 19863; mouse RMA -S cell line described by Ljunggren et al. (Ljunggren and Karre, 1985).
優選情況是,宿主細胞在轉染前基本上不表達 MHC I 類分子。刺激因數細胞還優選為表達對 T 細胞共刺激信號起到重要作用的分子,如,B7.1、B7.2、ICAM-1 和 LFA 3 中的任一種分子。大量 MHC I 類分子和共刺激分子的核酸序列可從 GenBank 和 EMBL 資料庫中公開獲得。Preferably, the host cells do not substantially express MHC class I molecules prior to transfection. The stimulatory factor cells also preferably express molecules that are important for T cell costimulatory signaling, such as any of B7.1, B7.2, ICAM-1 and LFA3. Nucleic acid sequences for numerous MHC class I molecules and costimulatory molecules are publicly available from GenBank and EMBL repositories.
當 MHC I 類表位用作一種抗原時,T 細胞為 CD8 陽性 T 細胞。When an MHC class I epitope is used as an antigen, the T cells are CD8 positive T cells.
如果抗原表現細胞受到轉染而表達這種表位,則優選的細胞包括一個表達載體,該載體有能力表達含 SEQ ID NO:1 至 SEQ ID NO:161 的肽或變體氨基酸序列。If an antigen-expressing cell is transfected to express such an epitope, the preferred cell includes an expression vector capable of expressing a peptide or variant amino acid sequence comprising SEQ ID NO: 1 to SEQ ID NO: 161.
可使用其他一些方法來體外生成 T 細胞。例如,自體腫瘤浸潤性淋巴細胞可用于生成 CTL。Plebanski 等人在 (Plebanski et al., 1995) 使用自體外周血淋巴細胞 (PLB) 制得 T 細胞。另外,也可能用肽或多肽脈衝處理樹突狀細胞或通過與重組病毒感染而製成自體 T 細胞。此外,B 細胞可用於製備自體 T 細胞。此外,用肽或多肽脈衝處理或用重組病毒感染的巨噬細胞可用於配製自體 T 細胞。S. Walter 等人在 (Walter et al., 2003) 中描述了通過使用人工抗原表現細胞 (aAPC) 體外啟動 T 細胞,這也是生成作用於所選肽的T 細胞的一種合適方法。在本發明中,根據生物素:鏈黴素生物化學方法通過將預製的MHC:肽複合物耦合到聚苯乙烯顆粒(微球)而生成 aAPC。該系統實現了對 aAPC 上的 MHC 密度進行精確調節,這使得可以在血液樣本中選擇地引發高或低親合力的高效抗原特異性 T 細胞反應。除了 MHC:肽複合物外,aAPC 還應攜運含共刺激活性的其他蛋白,如耦合至表面的抗-CD28 抗體。此外,此類基於 aAPC 的系統往往需要加入適當的可溶性因數,例如,諸如白細胞介素 12 的細胞因數。Several other methods can be used to generate T cells in vitro. For example, autologous tumor-infiltrating lymphocytes can be used to generate CTLs. Plebanski et al. (Plebanski et al., 1995) used autologous peripheral blood lymphocytes (PLB) to generate T cells. Alternatively, it is also possible to pulse dendritic cells with peptides or polypeptides or to generate autologous T cells by infection with recombinant viruses. In addition, B cells can be used to generate autologous T cells. In addition, macrophages pulsed with peptides or polypeptides or infected with recombinant viruses can be used to formulate autologous T cells. S. Walter et al. (Walter et al., 2003) describe in vitro priming of T cells by using artificial antigen-expressing cells (aAPCs), which is also a suitable method to generate T cells that act on selected peptides. In the present invention, aAPC is generated by coupling preformed MHC:peptide complexes to polystyrene particles (microspheres) according to the biotin:streptomycin biochemical method. The system enables precise modulation of MHC density on aAPCs, which allows selective elicitation of high- or low-affinity antigen-specific T cell responses in blood samples. In addition to the MHC:peptide complex, aAPC should also carry other proteins with co-stimulatory activity, such as anti-CD28 antibodies coupled to the surface. Furthermore, such aAPC-based systems often require the addition of appropriate soluble factors, eg, cytokines such as interleukin-12.
也可用同種異體細胞制得 T 細胞,在 WO 97/26328 中詳細描述了一種方法,以參考文獻方式併入本文。例如,除了果蠅細胞和 T2 細胞,也可用其他細胞來表現肽,如 CHO 細胞、杆狀病毒感染的昆蟲細胞、細菌、酵母、牛痘感染的靶細胞。此外,也可使用植物病毒(例如,參閱 Porta 等人在 (Porta et al., 1994) 中描述了將豇豆花葉病毒開發為一種表現外來肽的高產系統。T cells can also be generated from allogeneic cells, a method is described in detail in WO 97/26328, incorporated herein by reference. For example, in addition to Drosophila cells and T2 cells, other cells can also be used to express peptides, such as CHO cells, baculovirus-infected insect cells, bacteria, yeast, vaccinia-infected target cells. In addition, plant viruses can also be used (see, for example, Porta et al. (Porta et al., 1994) describing the development of cowpea mosaic virus as a high-yield system expressing foreign peptides.
被啟動的 T 細胞直接針對本發明中的肽,有助於治療。因此,本發明的另一方面提出了用本發明前述方法制得的啟動 T 細胞。Activated T cells are directed against the peptides of the present invention, facilitating therapy. Accordingly, another aspect of the present invention proposes prime T cells produced by the aforementioned method of the present invention.
按上述方法製成的啟動 T 細胞將會有選擇性地識別異常表達含 SEQ ID NO:1 至 SEQ ID NO 161 氨基酸序列的多肽。The prime T cells prepared by the above method will selectively recognize the abnormally expressed polypeptides containing the amino acid sequences of SEQ ID NO: 1 to SEQ ID NO 161.
優選情況是,T 細胞通過與其含 HLA/肽複合物的 TCR 相互作用(如,結合)而識別該細胞。T 細胞是殺傷患者靶細胞方法中有用的細胞,其靶細胞異常表達含本發明中氨基酸序列的多肽。此類患者給予有效量的啟動 T 細胞。給予患者的 T 細胞可能源自該患者,並按上述方法啟動(即,它們為自體 T 細胞)。或者,T 細胞不是源自該患者,而是來自另一個人。當然,優選情況是該供體為健康人。發明人使用「健康個人」系指一個人一般狀況良好,優選為免疫系統合格,更優選為無任何可很容易測試或檢測到的疾病。Preferably, the T cell recognizes the cell by interacting (eg, binding) to its TCR containing the HLA/peptide complex. T cells are useful in methods of killing target cells in patients, whose target cells abnormally express the polypeptides comprising the amino acid sequences of the present invention. Such patients are given an effective amount of priming T cells. T cells administered to a patient may be derived from that patient and primed as described above (ie, they are autologous T cells). Alternatively, the T cells were not derived from the patient, but from another person. Of course, it is preferred that the donor is a healthy human. The inventors use a "healthy individual" to mean a person who is generally in good health, preferably with a competent immune system, more preferably free of any disease that can be readily tested or detected.
根據本發明,CD8-陽性 T 細胞的體內靶細胞可為腫瘤細胞(有時表達 MHC-II 類抗原)和/或腫瘤周圍的基質細胞(腫瘤細胞)(有時也表達 MHC-II 類抗原; (Dengjel et al., 2006))。According to the present invention, the in vivo target cells of CD8-positive T cells may be tumor cells (sometimes expressing MHC class II antigens) and/or stromal cells (tumor cells) surrounding the tumor (sometimes also expressing MHC class II antigens; (Dengjel et al., 2006)).
本發明所述的 T 細胞可用作治療性組合物中的活性成分。因此,本發明也提出了一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明中氨基酸序列的多肽,該方法包括給予患者上述有效量的 T 細胞。The T cells of the present invention can be used as active ingredients in therapeutic compositions. Therefore, the present invention also provides a method for killing target cells of a patient, wherein the target cells of the patient abnormally express the polypeptide containing the amino acid sequence of the present invention, and the method comprises administering the above-mentioned effective amount of T cells to the patient.
發明人所用的「異常表達」的意思還包括,與正常表達水準相比,多肽過量表達,或該基因在源自腫瘤的組織中未表達,但是在該腫瘤中卻表達。「過量表達」系指多肽水準至少為正常組織中的 1.2 倍;優選為至少為正常組織中的 2 倍,更優選為至少 5 或 10 倍。"Aberrantly expressed" as used by the inventors also means that the polypeptide is overexpressed compared to normal expression levels, or that the gene is not expressed in the tumor-derived tissue, but is expressed in the tumor. "Overexpressed" means that the polypeptide level is at least 1.2-fold higher than in normal tissue; preferably at least 2-fold, more preferably at least 5- or 10-fold higher than in normal tissue.
T 細胞可用本領域已知的方法制得(如,上述方法)。T cells can be produced by methods known in the art (eg, methods described above).
T 細胞繼轉移方案為本領域所熟知的方案。綜述可發現於:Gattioni et al. 和 Morgan et al. (Gattinoni et al., 2006; Morgan et al., 2006)。T cell adoptive transfer protocols are well known in the art. Reviews can be found in: Gattioni et al. and Morgan et al. (Gattioni et al., 2006; Morgan et al., 2006).
本發明的另一個方面包括使用與 MHC 複合的肽,以生成 T 細胞受體,其核酸被克隆並被引入至宿主細胞,優選為 T 細胞。然後,該通過基因工程改變的 T 細胞可轉給患者用於癌症治療。Another aspect of the invention includes the use of peptides complexed with MHC to generate T cell receptors, the nucleic acid of which is cloned and introduced into host cells, preferably T cells. The genetically engineered T cells can then be transferred to patients for cancer treatment.
本發明的任一分子(即肽、核酸、抗體、表達載體、細胞,啟動 T 細胞、T 細胞受體或編碼核酸)都有益於治療疾病,其特點在於細胞逃避免疫反應的打擊。因此,本發明的任一分子都可用作藥劑或用於製造藥劑。這種分子可單獨使用也可與本發明中的其他分子或已知分子聯合使用。Any of the molecules of the present invention (ie, peptides, nucleic acids, antibodies, expression vectors, cells, priming T cells, T cell receptors or encoding nucleic acids) are useful in the treatment of diseases characterized by cells evading the blow of an immune response. Thus, any molecule of the present invention can be used as a medicament or for the manufacture of a medicament. This molecule can be used alone or in combination with other molecules of the invention or known molecules.
本發明還涉及一種套件,其包括: (a) 一個容器,包含上述溶液或凍乾粉形式的藥物組合物; (b) 可選的第二個容器,其含有凍乾粉劑型的稀釋劑或重組溶液;和 (c) 可選的(i)溶液使用或(ii)重組和/或凍乾製劑使用的說明。 The present invention also relates to a kit comprising: (a) a container containing the pharmaceutical composition described above in the form of a solution or lyophilized powder; (b) an optional second container containing the diluent or reconstituted solution in the lyophilized powder dosage form; and (c) Instructions for optional (i) use of solutions or (ii) use of reconstituted and/or lyophilized formulations.
該套件還步包括一個或多個 (iii) 緩衝劑,(iv) 稀釋劑,(v) 過濾器,(vi) 針,或 (v) 注射器。容器最好是瓶子、小瓶、注射器或試管,可以為多用途容器。藥物組合物最好是凍乾的。The kit also includes one or more of (iii) buffers, (iv) diluents, (v) filters, (vi) needles, or (v) syringes. The container is preferably a bottle, vial, syringe or test tube, and can be a multipurpose container. The pharmaceutical composition is preferably lyophilized.
本發明中的套件優選包含一種置於合適容器中的凍乾製劑以及重組和/或使用說明。適當的容器包括,例如瓶子、西林瓶 (如雙室瓶)、注射器 (如雙室注射器) 和試管。該容器可能由多種材料製成,如玻璃或塑膠。試劑盒和/或容器最好有容器或關於容器的說明書,指明重組和/或使用的方向。例如,標籤可能表明凍乾劑型將重組為上述肽濃度。該標籤可進一步表明製劑用於皮下注射。The kits of the present invention preferably contain a lyophilized formulation in a suitable container along with instructions for reconstitution and/or use. Suitable containers include, for example, bottles, vials (eg, dual-chamber vials), syringes (eg, dual-chamber syringes), and test tubes. The container may be made of various materials, such as glass or plastic. The kit and/or container preferably has a container or instructions for the container, indicating directions for reconstitution and/or use. For example, the label may indicate that the lyophilized dosage form will be reconstituted to the above peptide concentrations. The label may further indicate that the formulation is for subcutaneous injection.
存放製劑的容器可使用多用途西林瓶,使得可重複給予(例如,2-6 次)重組劑型。該套件可進一步包括裝有合適稀釋劑(如碳酸氫鈉溶液)的第二個容器。The container for the formulation may use a multi-purpose vial, allowing repeated administration (eg, 2-6 times) of the reconstituted dosage form. The kit may further include a second container containing a suitable diluent such as sodium bicarbonate solution.
稀釋液和凍乾製劑混合後,重組製劑中的肽終濃度優選為至少 0.15 mg/mL/肽 (=75µg),不超過 3 mg/mL/肽 (=1500µg)。該套件還可包括商業和用戶角度來說可取的其他材料,包括其他緩衝劑、稀釋劑,過濾器、針頭、注射器和帶有使用說明書的包裝插頁。After mixing the diluent and lyophilized formulation, the final peptide concentration in the reconstituted formulation is preferably at least 0.15 mg/mL/peptide (=75µg) and not more than 3 mg/mL/peptide (=1500µg). The kit may also include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
本發明中的套件可能有一個單獨的容器,其中包含本發明所述的藥物組合物製劑,該製劑可有其他成分(例如,其他化合物或及其藥物組合物),也可無其他成分,或者每種成分都有其不同容器。The kits of the present invention may have a single container containing a pharmaceutical composition formulation of the present invention, which may or may not have other ingredients (eg, other compounds or pharmaceutical compositions thereof), or Each ingredient has its own container.
優選情況是,本發明的套件包括與本發明的一種製劑,包裝後與第二種化合物(如佐劑(例如 GM-CSF)、化療藥物、天然產品、激素或拮抗劑、抗血管生成劑或抑制劑、凋亡誘導劑或螯合劑)或其藥物組合物聯合使用。該套件的成分可進行預絡合或每種成分在給予患者之前可放置於單獨的不同容器。該套件的成分可以是一種或多種溶液,優選為水溶液,更優選為無菌水溶液。該套件的成分也可為固體形式,加入合適的溶劑後轉換為液體,最好放置於另一個不同的容器中。Preferably, the kit of the present invention comprises one formulation of the present invention, packaged with a second compound (eg, an adjuvant (eg, GM-CSF), a chemotherapeutic drug, a natural product, a hormone or antagonist, an anti-angiogenic agent or inhibitors, apoptosis inducers or chelators) or their pharmaceutical compositions in combination. The components of the kit may be pre-complexed or each component may be placed in a separate distinct container prior to administration to the patient. The components of the kit may be one or more solutions, preferably aqueous solutions, more preferably sterile aqueous solutions. The components of the kit can also be in solid form, which can be converted to liquid after adding a suitable solvent, preferably in a different container.
治療套件的容器可能為西林瓶、試管、燒瓶、瓶子、注射器、或任何其他盛裝固體或液體的工具。通常,當成分不只一種時,套件將包含第二個西林瓶或其他容器,使之可以單獨定量。該套件還可能包含另一個裝載藥用液體的容器。優選情況是,治療套件將包含一個設備(如,一個或多個針頭、注射器、滴眼器、吸液管等),使得可注射本發明的藥物(本套件的組合物)。The container of the treatment kit may be a vial, test tube, flask, bottle, syringe, or any other means of holding solids or liquids. Often, when there is more than one ingredient, the kit will contain a second vial or other container to allow for individual dosing. The kit may also contain another container for medicinal liquids. Preferably, the treatment kit will contain a device (eg, one or more needles, syringes, eye droppers, pipettes, etc.) to enable the medicament of the invention (the composition of the kit) to be injected.
本發明的藥物配方適合以任何可接受的途徑進行肽給藥,如口服(腸道)、鼻內、眼內、皮下、皮內、肌內,靜脈或經皮給藥。優選為皮下給藥,最優選為皮內給藥,也可通過輸液泵給藥。The pharmaceutical formulations of the present invention are suitable for peptide administration by any acceptable route, such as oral (enteral), intranasal, intraocular, subcutaneous, intradermal, intramuscular, intravenous or transdermal administration. Subcutaneous administration is preferred, and intradermal administration is most preferred, but can also be administered by infusion pump.
由於本發明的肽從胰腺癌中分離而得,因此,本發明的藥劑優選用於治療胰腺癌。Since the peptide of the present invention is isolated from pancreatic cancer, the agent of the present invention is preferably used for the treatment of pancreatic cancer.
本發明進一步涉及為個體患者製備個體化藥物的一種方法,其中包括:製造含選自預篩選 TUMAP 存儲庫至少一種肽的藥物組合物,其中藥物組合物中所用的至少一種肽選擇為適合於個體患者。在一項實施方案中,藥物組合物為一種疫苗。該方法也可以改動以產生下游應用的 T 細胞克隆物,如:TCR 隔離物或可溶性抗體和其他治療選擇。The present invention further relates to a method of preparing a personalized medicine for an individual patient, comprising: making a pharmaceutical composition comprising at least one peptide selected from the pre-screened TUMAP repository, wherein the at least one peptide used in the pharmaceutical composition is selected to be suitable for the individual patient. In one embodiment, the pharmaceutical composition is a vaccine. The method can also be adapted to generate T cell clones for downstream applications such as: TCR isolates or soluble antibodies and other therapeutic options.
「個體化藥物」系指專門針對個體患者的治療,將僅用於該等個體患者,包括個體化活性癌症疫苗以及使用自體組織的過繼細胞療法。"Personalized medicine" refers to treatments that are specific to, and will be used only for, individual patients, including individualized live cancer vaccines and adoptive cell therapy using autologous tissue.
如本文所述,「存儲庫」應指已經接受免疫原性預篩查和/或在特定腫瘤類型中過量表現的一組或一系列肽。「存儲庫」一詞並不暗示,疫苗中包括的特定肽已預先製造並儲存於物理設備中,雖然預期有這種可能性。明確預期所述肽可以用於新製造每種個體化疫苗,也可能被預先製造和儲存。存儲庫(例如,資料庫形式)由腫瘤相關肽組成,其在各種 HLA-A HLA-B 和 HLA-C 等位元基因胰腺癌患者的腫瘤組織中高度過度表達。其可能含有包括 MHC I 類和 MHC II 類肽或拉長的 MHC I 類肽。除了從幾種胰腺癌樣本中採集的腫瘤相關肽外,存儲庫還可能包含 HLA-A*02 和 HLA-A*24 標記肽。這些肽可對 TUMAP 誘導的 T 細胞免疫進行量化比較,從而可得出疫苗抗腫瘤反應能力的重要結論。其次,在沒有觀察到來自患者「自身」抗原 TUMAP 的任何疫苗誘導的 T 細胞反應時,它們可作為來自「非自身」抗原的重要陽性對照肽。第三,它還可對患者的免疫功能狀態得出結論。As used herein, a "repository" shall refer to a set or series of peptides that have been prescreened for immunogenicity and/or overexpressed in a particular tumor type. The term "repository" does not imply that the specific peptide included in the vaccine has been pre-manufactured and stored in a physical facility, although this possibility is expected. It is expressly contemplated that the peptides can be used in the new manufacture of each individualized vaccine, and possibly pre-manufactured and stored. Repositories (eg, database formats) consist of tumor-associated peptides that are highly overexpressed in tumor tissue from pancreatic cancer patients with various HLA-A, HLA-B and HLA-C alleles. It may contain MHC class I and MHC class II peptides or elongated MHC class I peptides. In addition to tumor-associated peptides collected from several pancreatic cancer samples, the repository may also contain HLA-
存儲庫的 TUMAP 通過使用一種功能基因組學方法進行鑒定,該方法結合了基因表達分析、質譜法和 T 細胞免疫學 (XPresident ®)。該方法確保了只選擇真實存在于高百分比腫瘤但在正常組織中不表達或僅很少量表達的 TUMAP 用於進一步分析。對於初始肽的選擇,胰腺癌樣本和健康供體的血液以循序漸進的方法進行分析:
1. 惡性材料的 HLA 配體用質譜法確定
2. 使用全基因組信使核糖核酸 (mRNA) 表達分析法用於確定惡性腫瘤組織(胰腺癌)與一系列正常器官和組織相比過度表達的基因。
3. 確定的 HLA 配體與基因表達資料進行比較。腫瘤組織上過度表現或選擇性表現的肽,優選為第 2 步中檢測到的選擇性表達或過量表達基因所編碼的考慮為多肽疫苗的合適候選 TUMAP。
4. 文獻檢索以確定更多證據以支持確認為 TUMP 的肽的相關性
5. 過度表達在 mRNA 水準的相關性由腫瘤組織第 3 步選定的 TUMAP 重新檢測而確定,並且在健康組織上缺乏(或不經常)檢測。
6. 為了評估通過選定的肽誘導體內 T 細胞反應是否可行,使用健康供體以及胰腺癌患者的人 T 細胞進行體外免疫原性測定。
The repository's TUMAP was identified using a functional genomics approach that combines gene expression analysis, mass spectrometry, and T-cell immunology (XPresident ®). This method ensures that only TUMAPs that are truly present in a high percentage of tumors but are not expressed or are expressed only in small amounts in normal tissues are selected for further analysis. For initial peptide selection, pancreatic cancer samples and blood from healthy donors were analyzed in a step-by-step approach:
1. HLA Ligands of Malignant Materials Determined by Mass Spectrometry
2. Genome-wide messenger ribonucleic acid (mRNA) expression analysis was used to identify genes overexpressed in malignant tumor tissue (pancreatic cancer) compared to a range of normal organs and tissues.
3. The identified HLA ligands are compared to the gene expression data. The peptides overexpressed or selectively expressed on tumor tissue, preferably TUMAPs encoded by the selectively expressed or overexpressed genes detected in step 2, are considered suitable candidates for polypeptide vaccines.
4. Literature search to identify additional evidence to support the relevance of peptides identified as
一方面,在將所述肽加入存儲庫之前,對其進行篩查以瞭解免疫原性。舉例來說(但不限於此),納入存儲庫的肽的免疫原性的確定方法包括體外 T 細胞啟動,具體為:用裝載肽/MHC 複合物和抗 CD28 抗體的人工抗原表現細胞反復刺激來自健康供體的 CD8+ T 細胞。In one aspect, the peptides are screened for immunogenicity prior to adding them to the repository. By way of example, but not limitation, methods for determining the immunogenicity of the peptides included in the repository include in vitro T cell priming by repeated stimulation with artificial antigen-expressing cells loaded with peptide/MHC complexes and anti-CD28 antibodies from CD8+ T cells from healthy donors.
這種方法優選用於罕見癌症以及有罕見表達譜的患者。與含目前開發為固定組分的多肽雞尾酒相反的是,存儲庫可將腫瘤中抗原的實際表達於疫苗進行更高程度的匹配。在多目標方法中,每名患者將使用幾種「現成」肽的選定單一肽或組合。理論上來說,基於從 50 抗原肽庫中選擇例如 5 種不同抗原肽的一種方法可提供大約 170萬 種可能的藥物產品 (DP) 組分。This approach is preferably used for rare cancers and patients with rare expression profiles. In contrast to cocktails containing peptides that are currently developed as fixed components, repositories allow for a higher degree of matching between the actual expression of antigens in tumors and vaccines. In a multi-target approach, each patient will use a selected single peptide or combination of several "off-the-shelf" peptides. In theory, a method based on the selection of e.g. 5 different antigenic peptides from a library of 50 antigenic peptides could provide approximately 1.7 million possible drug product (DP) components.
在一方面,選擇所述肽用於疫苗,其基於個體患者的適合性,並使用本發明此處或後文所述的方法。In one aspect, the peptides are selected for use in vaccines based on the suitability of the individual patient and using the methods of the invention described herein or hereinafter.
HLA 表型、轉錄和肽組學資料從患者的腫瘤材料和血液樣本中收集,以確定最合適每名患者且含有「存儲庫」和患者獨特(即突變)TUMAP 的肽。將選擇的那些肽選擇性地或過度表達于患者腫瘤中,並且可能的情況下,如果用患者個體 PBMC 進行檢測,則表現出很強的體外免疫原性。HLA phenotypic, transcriptomic, and peptidomics data were collected from patient tumor material and blood samples to identify peptides that were most appropriate for each patient and contained "repositories" and patient-unique (ie, mutated) TUMAPs. Those peptides of choice were selectively or overexpressed in patient tumors and, where possible, exhibited strong in vitro immunogenicity if tested with individual patient PBMCs.
優選的情況是,疫苗所包括的肽的一種確定方法包括:(a) 識別由來自個體患者腫瘤樣本表現的腫瘤相關肽 (TUMAP);(b) 將 (a) 中鑒定的肽與上述肽的存儲庫(資料庫)進行比對;且 (c) 從與患者中確定的腫瘤相關肽相關的存儲庫(資料庫)中選擇至少一種肽。例如,腫瘤樣本表現的 TUMAP 的鑒定方法有:(a1) 將來自腫瘤樣本的表達資料與所述腫瘤樣本組織類型相對應的正常組織樣本的表達資料相比對,以識別腫瘤組織中過量表達或異常表達的蛋白;以及 (a2) 將表達資料與結合到腫瘤樣本中 I 類 MHC 和/或 II 類分子的 MHC 配體序列想關聯,以確定來源於腫瘤過量表達或異常表達的蛋白質的 MHC 配體。優選情況是,MHC 配體的序列的確定方法是:洗脫來自腫瘤樣本分離的 MHC 分子結合肽,並測序洗脫配體。優選情況是,腫瘤樣本和正常組織從同一患者獲得。Preferably, a method for determining the peptides included in the vaccine comprises: (a) identifying tumor-associated peptides (TUMAPs) expressed by tumor samples from individual patients; (b) combining the peptides identified in (a) with the peptides described above. and (c) selecting at least one peptide from a repository (repository) associated with tumor-associated peptides identified in the patient. For example, methods for identifying TUMAPs expressed by tumor samples include: (a1) Comparing expression data from tumor samples with expression data from normal tissue samples corresponding to the tissue type of said tumor samples to identify overexpressed or aberrantly expressed proteins; and (a2) correlate expression data with MHC ligand sequences that bind to MHC class I and/or class II molecules in tumor samples to identify MHC ligands derived from proteins overexpressed or aberrantly expressed in tumors body. Preferably, the sequence of the MHC ligand is determined by eluting the MHC molecule-binding peptide isolated from the tumor sample and sequencing the eluted ligand. Preferably, the tumor sample and normal tissue are obtained from the same patient.
除了使用存儲庫(資料庫)模型選擇肽以外,或作為一種替代方法,TUMAP 可能在新患者中進行鑒定,然後列入疫苗中。作為一種實施例,患者中的候選 TUMAP 可通過以下方法進行鑒定:(a1) 將來自腫瘤樣本的表達資料與所述腫瘤樣本組織類型相對應的正常組織樣本的表達資料相比對,以識別腫瘤組織中過量表達或異常表達的蛋白;以及 (a2) 將表達資料與結合到腫瘤樣本中 I 類 MHC 和/或 II 類分子的 MHC 配體序列想關聯,以確定來源於腫瘤過量表達或異常表達的蛋白質的 MHC 配體。作為另一實施例,蛋白的鑒定方法為可包含突變,其對於腫瘤樣本相對于個體患者的相應正常組織是獨特的,並且 TUMAP 可通過特異性靶向作用於變異來鑒定。例如,腫瘤以及相應正常組織的基因組可通過全基因組測序方法進行測序:為了發現基因蛋白質編碼區域的非同義突變,從腫瘤組織中萃取基因組 DNA 和 RNA,從外周血單核細胞 (PBMC) 中提取正常非突變基因組種系 DNA。運用的 NGS 方法只限于蛋白編碼區的重測序(外顯子組重測序)。為了這一目的,使用供應商提供的靶序列富集試劑盒來捕獲來自人樣本的外顯子 DNA,隨後使用 HiSeq2000(Illumina公司)進行測序。此外,對腫瘤的 mRNA 進行測序,以直接定量基因表達,並確認突變基因在患者腫瘤中表達。得到的數以百萬計的序列讀數通過軟體演算法處理。輸出列表中包含突變和基因表達。腫瘤特異性體突變通過與 PBMC 衍生的種系變化比較來確定,並進行優化。然後,為了存儲庫可能測試新確定的肽瞭解如上所述的免疫原性,並且選擇具有合適免疫原性的候選 TUMAP 用於疫苗。In addition to, or as an alternative to, selection of peptides using a repository (repository) model, TUMAPs may be identified in new patients and then included in vaccines. As one example, candidate TUMAPs in a patient can be identified by: (a1) matching the expression profile from a tumor sample with the expression profile of a normal tissue sample corresponding to the tissue type of the tumor sample to identify a tumor Proteins that are overexpressed or aberrantly expressed in tissues; and (a2) correlate expression data with sequences of MHC ligands that bind to MHC class I and/or class II molecules in tumor samples to identify tumor-derived overexpressed or aberrantly expressed MHC ligands of proteins. As another example, proteins can be identified by methods that can contain mutations that are unique to a tumor sample relative to the corresponding normal tissue of an individual patient, and TUMAPs can be identified by specifically targeting the mutations. For example, the genomes of tumors and corresponding normal tissues can be sequenced by whole-genome sequencing methods: To discover non-synonymous mutations in the protein-coding regions of genes, genomic DNA and RNA are extracted from tumor tissues, and extracted from peripheral blood mononuclear cells (PBMCs). Normal non-mutated genomic germline DNA. The NGS methods used are limited to resequencing of protein-coding regions (exome resequencing). For this purpose, exonic DNA from human samples was captured using a target enrichment kit provided by the supplier and subsequently sequenced using HiSeq2000 (Illumina). In addition, tumor mRNA is sequenced to directly quantify gene expression and confirm that mutated genes are expressed in patient tumors. The resulting millions of sequence reads are processed through software algorithms. Mutations and gene expression are included in the output list. Tumor-specific somatic mutations were identified by comparison to PBMC-derived germline changes and optimized. The newly identified peptides may then be tested for immunogenicity as described above for the repository, and candidate TUMAPs with suitable immunogenicity are selected for use in vaccines.
在一個示範實施方案中,疫苗中所含肽通過以下方法確定:(a) 用上述方法識別由來自個體患者腫瘤樣本表現的腫瘤相關肽 (TUMAP);(b) 將 (a) 中鑒定的肽與進行腫瘤(與相應的正常組織相比)免疫原性和過量表現預篩查肽的存儲庫進行比對;(c) 從與患者中確定的腫瘤相關肽相關的存儲庫中選擇至少一種肽;及 (d) 可選地在 (a) 中選擇至少一種新確定的肽,確認其免疫原性。In an exemplary embodiment, the peptides contained in the vaccine are determined by: (a) identifying tumor-associated peptides (TUMAPs) expressed by tumor samples from individual patients using the methods described above; (b) combining the peptides identified in (a) Alignment with a repository of pre-screened peptides for tumor (compared to corresponding normal tissue) immunogenicity and overrepresentation; (c) selection of at least one peptide from a repository associated with tumor-associated peptides identified in patients and (d) optionally selecting at least one newly identified peptide in (a) and confirming its immunogenicity.
在一個示範實施方案中,疫苗中所含肽通過以下方法確定:(a) 識別由來自個體患者腫瘤樣本表現的腫瘤相關肽 (TUMAP);以及 (b) 在 (a) 中選擇至少一種新確定的肽,並確認其免疫原性。In an exemplary embodiment, the peptides contained in the vaccine are determined by: (a) identifying tumor-associated peptides (TUMAPs) expressed by tumor samples from individual patients; and (b) selecting at least one newly determined in (a) peptides and confirm their immunogenicity.
一旦選定了用於個體化肽疫苗的肽時,則產生疫苗。該疫苗優選為一種液體製劑,包括溶解於 20-40% DMSO 之間,優選為約 30-35% DMSO,例如,約 33% DMSO 中的個體肽。Once the peptides for the individualized peptide vaccine are selected, the vaccine is produced. The vaccine is preferably a liquid formulation comprising the individual peptides dissolved in between 20-40% DMSO, preferably about 30-35% DMSO, eg, about 33% DMSO.
列入產品的每種肽都溶於 DMSO 中。單個肽溶液濃度的選擇取決於要列入產品中的肽的數量。單肽-DMSO 溶液均等混合,以實現一種溶液中包含所有的肽,且濃度為每肽~2.5 mg/ml。然後該混合溶液按照1:3比例用注射用水進行稀釋,以達到在 33% DMSO 中每肽 0.826 mg/ml 的濃度。稀釋的溶液通過 0.22 μm 無菌篩檢程序進行過濾。從而獲得最終本體溶液。Each peptide listed in the product is dissolved in DMSO. The choice of individual peptide solution concentrations depends on the amount of peptide to be included in the product. The single peptide-DMSO solutions were mixed equally to achieve a solution containing all peptides at a concentration of ~2.5 mg/ml per peptide. The mixed solution was then diluted 1:3 with water for injection to achieve a concentration of 0.826 mg/ml per peptide in 33% DMSO. The diluted solution is filtered through a 0.22 μm sterile screening procedure. Thereby the final bulk solution is obtained.
最終本體溶液填充到小瓶中,在使用前儲存於-20℃下。一個小瓶包含 700 μL 溶液,其中每種肽含有 0.578 mg。其中的 500 μL(每種肽約 400 μg)將用於皮內注射。The final bulk solution was filled into vials and stored at -20°C until use. One vial contains 700 μL of solution containing 0.578 mg of each peptide. 500 μL of this (approximately 400 μg of each peptide) will be used for intradermal injection.
本發明的肽除了用於治療癌症,也可用於診斷。由於肽由胰腺癌樣本產生,並且已確定這些肽在正常組織中不存在或水準較低,因此這些肽可用於診斷癌症是否存在。In addition to their use in the treatment of cancer, the peptides of the present invention can also be used in diagnosis. Since the peptides are produced from pancreatic cancer samples and have been determined to be absent or at low levels in normal tissue, these peptides can be used to diagnose the presence or absence of cancer.
血液樣本中組織活檢物含請求的肽,可有助於病理師診斷癌症。用抗體、質譜或其他本領域內已知的方法檢測某些肽可使病理師判斷該組織樣本為惡性的還是炎症或一般病變,也可用作胰腺癌的生物標誌物。肽基團的表現使得能對病變組織進行分類或進一步分成子類。Tissue biopsies in blood samples contain the requested peptides, which may aid pathologists in diagnosing cancer. Detection of certain peptides using antibodies, mass spectrometry or other methods known in the art allows the pathologist to determine whether the tissue sample is malignant or inflammatory or general, and can also be used as biomarkers for pancreatic cancer. The presentation of the peptide groups enables classification or further subclassification of diseased tissue.
對病變標本中肽的檢測使得能對免疫系統治療方法的利益進行判斷,特別是如果 T- 淋巴細胞已知或預計與作用機制有關。MHC 表達的缺失是一種機制,充分說明了哪些受感染的惡性細胞逃避了免疫監視。因此,肽的表現表明,分析過的細胞並沒有利用這種機制。Detection of peptides in lesion specimens allows judgment of interest in immune system therapeutic approaches, especially if T-lymphocytes are known or predicted to be involved in the mechanism of action. Loss of MHC expression is a mechanism by which infected malignant cells escape immune surveillance. Thus, the performance of the peptides indicated that the analyzed cells did not utilize this mechanism.
本發明的肽可用於分析淋巴細胞對肽的反應(如 T 細胞反應),或抗體對肽或 MHC 分子絡合的肽發生的反應。這些淋巴細胞反應可以作為預後指標,決定是否採取進一步的治療。這些反應也可以用作免疫療法中的替代反應指標,旨在以不同方式誘導淋巴細胞反應,如接種蛋白疫苗、核酸、自體材料、淋巴細胞過繼轉移。基因治療中,淋巴細胞對肽發生的反應可以在副作用的評估中考慮。淋巴細胞反應監測也可能成為移植療法隨訪檢查中的一種有價值的工具,如,用於檢測移植物抗宿主和宿主抗移植物疾病。The peptides of the invention can be used to analyze lymphocyte responses to peptides (eg, T cell responses), or antibody responses to peptides or peptides complexed with MHC molecules. These lymphocyte responses can be used as prognostic indicators to decide whether to take further treatment. These responses can also be used as surrogate response indicators in immunotherapy, aiming to induce lymphocyte responses in different ways, such as vaccination with protein, nucleic acid, autologous material, adoptive transfer of lymphocytes. In gene therapy, the response of lymphocytes to peptides can be considered in the assessment of side effects. Lymphocyte response monitoring may also be a valuable tool in follow-up examinations of transplant therapy, eg, for the detection of graft-versus-host and host-versus-graft disease.
下列描述優選方案的實施例將對本發明進行說明,並參照隨附圖表(但是不僅限於此)。考慮到本發明的目的,文中引用的所有參考文獻通過引用的方式併入在本文中。 實施例 實施例 1 細胞表面表現的腫瘤相關肽的識別和定量 組織樣本 The following examples describing preferred embodiments will illustrate the invention, with reference to (but not limited to) the accompanying figures. All references cited herein are hereby incorporated by reference for the purposes of the present invention. EXAMPLES Example 1 Identification and quantification of tumor-associated peptides expressed on cell surfaces in tissue samples
患者的腫瘤組織和細胞系獲得自德國蒂賓根大學醫院、德國海德堡大學醫院、德國NMI Reutlingen、MD Anderson 癌症中心, Houston, TX, USA。正常組織獲得自 Asterand, Detroit, USA 和 Royston, Herts, UK、Bio-Options Inc., CA, USA、BioServe, Beltsville, MD, USA、Capital BioScience Inc., Rockville, MD, USA、Geneticist Inc., Glendale, CA, USA、Tissue Solutions Ltd, Glasgow, Scotland, UK、日內瓦大學醫院、海德堡大學醫院、京都府立醫科大學 (KPUM)、慕尼克大學醫院、ProteoGenex Inc., Culver City, CA, USA、德國蒂賓根大學醫院。所有供體在手術或屍檢前都獲得了書面知情同意。切除後組織立即進行冷休克處理,在分離 TUMAP 前儲存於 -70°C 或以下。 從組織樣本中分離 HLA 肽 The patient's tumor tissue and cell lines were obtained from University Hospital Tübingen, Germany, University Hospital Heidelberg, Germany, NMI Reutlingen, Germany, MD Anderson Cancer Center, Houston, TX, USA. Normal tissues were obtained from Asterand, Detroit, USA and Royston, Herts, UK, Bio-Options Inc., CA, USA, BioServe, Beltsville, MD, USA, Capital BioScience Inc., Rockville, MD, USA, Geneticist Inc., Glendale , CA, USA, Tissue Solutions Ltd, Glasgow, Scotland, UK, Geneva University Hospital, Heidelberg University Hospital, Kyoto Prefectural University of Medicine (KPUM), Munich University Hospital, ProteoGenex Inc., Culver City, CA, USA, Tübing, Germany Root University Hospital. Written informed consent was obtained from all donors prior to surgery or autopsy. Tissues were cold-shocked immediately after excision and stored at -70°C or below until TUMAP isolation. Isolation of HLA peptides from tissue samples
根據方案 (Falk et al., 1991; Seeger et al., 1999) 略加修改,使用HLA-A*02特異性抗體BB7.2、HLA-A、HLA-B、HLAC特異性抗體W6/32、CNBr活化的瓊脂糖凝膠、酸處理和超濾方法以免疫沉澱法獲得了冷凍組織樣本的 HLA 肽庫。 質譜分析 According to the protocol (Falk et al., 1991; Seeger et al., 1999) with slight modifications, HLA-A*02 specific antibody BB7.2, HLA-A, HLA-B, HLAC specific antibody W6/32, HLA peptide libraries from frozen tissue samples were obtained by immunoprecipitation using CNBr-activated sepharose, acid treatment, and ultrafiltration. Mass Spectrometry
獲得的 HLA 肽庫根據其疏水性用反相色譜 (nanoAcquity UPLC system, Waters) 分離,洗脫肽用裝有電噴霧源的 LTQ- velos 融合雜交質譜 (ThermoElectron) 進行了分析。肽庫被直接載入填充有 1.7 µm C18 反相材料 (Waters) 的分析用熔煉石英微毛細管柱(75 µm 內徑x 250 mm),應用流速為 400 nL 每分鐘。隨後,使用來自流速為 300 nL每分鐘、濃度為10% 至 33% 溶劑 B 中的兩步180分鐘二元梯度法對肽進行分離。梯度由溶劑 A(含0.1% 甲酸的水)和溶劑 B(含0.1 % 甲酸的乙腈)。金鍍膜玻璃毛細管 (PicoTip, New Objective) 用於引入到納升電噴霧源。使用前 5 (TOP5) 策略在資料依賴模式下操作 LTQ-Orbitrap 質譜儀。簡言之,首先以高精確品質完全掃描在 orbitrap 開始一個掃描週期 (R= 30 000),之後用先前選定離子的動態排除技術在 orbitrap 中對 5 種含量最為豐富的前體離子進行 MS/MS 掃描 (R = 7500)。串聯質譜以 SEQUEST 和另一種手動控制器進行解讀。生成的自然肽破碎模式與合成序列相同參考肽的破碎模式進行比較後,確保了被識別的肽序列。The obtained HLA peptide library was separated by reversed-phase chromatography (nanoAcquity UPLC system, Waters) according to its hydrophobicity, and the eluted peptides were analyzed by LTQ-velos fusion hybrid mass spectrometer (ThermoElectron) equipped with an electrospray source. The peptide library was loaded directly onto an analytical fused silica microcapillary column (75 µm id x 250 mm) packed with 1.7 µm C18 reversed-phase material (Waters) at an applied flow rate of 400 nL per minute. The peptides were then separated using a two-step 180-minute binary gradient in solvent B at a flow rate of 300 nL per minute at concentrations ranging from 10% to 33%. The gradient consisted of solvent A (0.1 % formic acid in water) and solvent B (0.1 % formic acid in acetonitrile). Gold-coated glass capillaries (PicoTip, New Objective) were used for introduction into the nanoliter electrospray source. Operate the LTQ-Orbitrap mass spectrometer in data-dependent mode using the top 5 (TOP5) strategy. Briefly, a scan cycle (R = 30 000) was initiated in the orbitrap with a full scan of high accuracy quality, followed by MS/MS in the orbitrap using dynamic exclusion of previously selected ions for the 5 most abundant precursor ions Scan (R = 7500). Tandem mass spectra were interpreted with SEQUEST and another manual controller. The resulting fragmentation patterns of natural peptides were compared to those of a synthetic reference peptide of the same sequence to ensure the identified peptide sequence.
無標記相對 LC-MS定量通過離子計數(即通過LC-MS功能提取和分析)來進行 (Mueller et al., 2007)。該方法假定肽的 LC-MS 信號區域與樣本中其豐度相關。提取的特徵通過充電狀態去卷積和保留時間校準進行進一步處理 (Mueller et al., 2008; Sturm et al., 2008)。最後,所有的 LC-MS 特徵與序列鑒定結果交叉引用,以將不同樣本和組織的定量資料與肽呈遞特徵結合。定量資料根據集中資料以兩層方式進行正態化處理,以說明技術和生物學複製變異。因此,每個被識別的肽均可與定量資料相關,從而可得出樣本和組織之間的相對定量。此外,對候選肽獲得的所有定量資料進行手動檢查,以確保資料的一致性,並驗證自動化分析的準確度。對於每種肽,計算了表現圖,其顯示樣本平均表現量以及複製變化。這些特徵使胰腺癌樣本與正常組織樣本的基線值並列。示範性過度表現肽的表現譜示於圖 1 中。示範性肽的表現分數見表 8。
表 8:表現分數。該表列出了與一系列正常組織相比在腫瘤上非常高度過量表現 (+++)、與一系列正常組織相比在腫瘤上高度過量表現 (++) 或與一系列正常組織相比在腫瘤上過量表現 (+) 的 肽。
與正常細胞相比在腫瘤細胞上一種肽過度表現或特定表現足夠其在免疫治療中有效使用,一些肽為腫瘤特異性的,儘管存在其源蛋白也存在于正常組織中。但是,mRNA 表達譜增加了免疫治療目標肽選擇中其他級別的安全性。特別是對於具有高安全性風險的治療選擇,諸如親和力成熟的 TCR,理想的目標肽將來源於對該腫瘤獨一無二且不出現于正常組織中的蛋白。 RNA 來源與製備 Overexpression or specificity of a peptide on tumor cells compared to normal cells is sufficient for its effective use in immunotherapy, and some peptides are tumor-specific despite the presence of their source proteins also in normal tissues. However, mRNA expression profiling adds other levels of safety in immunotherapy target peptide selection. Especially for therapeutic options with high safety risks, such as affinity matured TCRs, the ideal target peptide would be derived from a protein unique to the tumor and not present in normal tissues. RNA source and preparation
手術切除組織標本按如上所述(參見實施例 1)在獲得每名患者的書面知情同意後提供。手術後立即速凍腫瘤組織標本,之後在液態氮中用杵臼勻漿。使用 TRI 試劑(Ambion 公司, Darmstadt,德國)之後用 RNeasy(QIAGEN公司,Hilden,德國)清理從這些樣本中製備總 RNA;這兩種方法都根據製造商的方案進行。Surgically resected tissue specimens were provided after obtaining written informed consent from each patient as described above (see Example 1). Tumor tissue samples were snap-frozen immediately after surgery and then homogenized with a pestle and mortar in liquid nitrogen. Total RNA was prepared from these samples using TRI reagent (Ambion, Darmstadt, Germany) followed by RNeasy (QIAGEN, Hilden, Germany) cleanup; both methods were performed according to the manufacturer's protocol.
健康人體組織中的總 RNA 從商業途徑獲得(Ambion公司,Huntingdon,英國;Clontech公司,海德堡,德國; Stratagene 公司,阿姆斯特丹,荷蘭;BioChain 公司,Hayward, CA, 美國)。混合數個人(2 至 123 個人)的 RNA,從而使每個人的 RNA 得到等加權。Total RNA in healthy human tissue was obtained from commercial sources (Ambion, Huntingdon, UK; Clontech, Heidelberg, Germany; Stratagene, Amsterdam, The Netherlands; BioChain, Hayward, CA, USA). Mix RNA from several individuals (2 to 123 individuals) so that each individual's RNA is equally weighted.
所有 RNA 樣本的品質和數量都在 Agilent 2100 Bioanalyzer 分析儀(Agilent 公司, Waldbronn,德國)上使用 RNA 6000 Pico LabChip Kit 試劑盒(Agilent 公司)進行評估。 微陣列實驗 The quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent). Microarray experiments
所有腫瘤和正常組織的 RNA 樣本都使用 Affymetrix Human Genome (HG) U133A 或HG-U133 Plus 2.0Affymetrix 寡核苷酸晶片(Affymetrix 公司,Santa Clara,CA,美國)進行基因表達分析。所有步驟都根據 Affymetrix 手冊進行。簡言之,如手冊中所述,使用 SuperScript RTII (Invitrogen 公司)以及 oligo-dT-T7 引物(MWG Biotech公司,Ebersberg, 德國)從 5–8 µg RNA中合成雙鏈 cDNA。用 BioArray High Yield RNA Transcript Labelling Kit (ENZO Diagnostics 公司, Farmingdale, NY, 美國)進行 U133A 測定或用 GeneChip IVT Labelling Kit (Affymetrix 公司)進行 U133 Plus 2.0 測定,之後用鏈黴親和素-藻紅蛋白和生物素化抗鏈黴素蛋白抗體(Molecular Probes 公司,Leiden,荷蘭)進行破碎、雜交和染色,這樣完成體外轉錄。用 Agilent 2500A GeneArray Scanner (U133A) 或 Affymetrix Gene-Chip Scanner 3000 (U133 Plus 2.0) 對圖像進行掃描,用 GCOS 軟體(Affymetrix公司)在所有參數默認設置情況下對資料進行分析。為了實現標準化,使用了 Affymetrix 公司提供的 100 種管家基因 (housekeeping gene)。相對表達值用軟體給定的 signal log ratio 進行計算,正常腎組織樣本的值任意設置為 1.0。本發明的代表性源基因在胰腺癌中高度過量表達的表達譜如圖 2 所示。進一步代表性基因的表達分數見表 9。
表 9 :表達分數。該表列出了與一系列正常組織相比在腫瘤上非常高度過量表達 (+++)、與一系列正常組織相比在腫瘤上高度過量表達 (++) 或與一系列正常組織相比在腫瘤上過量表達 (+) 的基因的肽。
為了獲得關於本發明 TUMAP 的免疫原性資訊,發明人使用體外 T 細胞擴增分析方法進行了研究,其中該分析方法基於使用裝載肽/MHC 複合物和抗CD28 抗體的人工抗原表現細胞 (aAPC) 進行反復刺激。用這種方法,發明人可顯示出本發明目前為止 22 種 HLA-A*0201 限制 TUMAP 具有免疫原性,這表明這些肽為對抗人 CD8+ 前體 T 細胞的 T 細胞表位(表 10)。 CD8+ T 細胞體外啟動 To obtain information on the immunogenicity of the TUMAPs of the present invention, the inventors conducted studies using an in vitro T cell expansion assay based on the use of artificial antigen-expressing cells (aAPCs) loaded with peptide/MHC complexes and anti-CD28 antibodies Repeat stimulation. Using this approach, the inventors were able to show that the 22 HLA-A*0201-restricted TUMAPs of the present invention to date are immunogenic, suggesting that these peptides are T cell epitopes against human CD8+ precursor T cells (Table 10). In vitro priming of CD8+ T cells
為了用載有肽-MHC複合物 (pMHC) 和抗 CD28 抗體的人工抗原表現細胞進行體外刺激,發明人首先從 University clinics Mannheim, Germany 中獲取健康供體 CD8 微珠 (Miltenyi Biotec, Bergisch-Gladbach, Germany) 通過積極選擇白細胞清除術後新鮮HLA-A*02 產物而分離出 CD8+ T 細胞。For in vitro stimulation with artificial antigen-expressing cells loaded with peptide-MHC complexes (pMHC) and anti-CD28 antibodies, the inventors first obtained healthy donor CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) from University clinics Mannheim, Germany. Germany) CD8+ T cells were isolated by aggressive selection of fresh HLA-
PBMC 和分離出的 CD8+ 淋巴細胞使用前在 T 細胞培養基 (TCM) 中培養,培養基包括 RPMI- Glutamax (Invitrogen公司,Karlsruhe,德國)並補充 10% 熱滅活人 AB 血清(PAN-Biotech 公司,Aidenbach,德國)、100U/ml 青黴素/ 100 µg/ml 鏈黴素(Cambrex公司,Cologne,德國),1mM 丙酮酸鈉(CC Pro公司,Oberdorla,德國)和20 µg/ml 慶大黴素(Cambrex公司)。在此步驟,2.5 ng/ml 的 IL-7 (PromoCell公司,Heidelberg,德國) 和 10 U / ml 的 IL- 2(Novartis Pharma 公司,Nürnberg,德國)也加入 TCM。PBMC and isolated CD8+ lymphocytes were cultured in T cell culture medium (TCM) containing RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) supplemented with 10% heat-inactivated human AB serum (PAN-Biotech, Aidenbach) prior to use. , Germany), 100 U/ml penicillin/100 µg/ml streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany), and 20 µg/ml gentamicin (Cambrex, Germany) ). At this step, 2.5 ng/ml of IL-7 (PromoCell, Heidelberg, Germany) and 10 U/ml of IL-2 (Novartis Pharma, Nürnberg, Germany) were also added to the TCM.
對於pMHC/抗-CD28 塗層珠的生成、T 細胞的刺激和讀出,使用每刺激條件四個不同 pMHC 分子以及每個讀出條件 8 個不同的 pMHC 分子在高度限定的體外系統中進行。For generation of pMHC/anti-CD28 coated beads, stimulation and readout of T cells, four different pMHC molecules per stimulation condition and eight different pMHC molecules per readout condition were performed in a highly defined in vitro system.
純化的共刺激小鼠 IgG2a 抗人 CD28 抗體 9.3 (Jung et al., 1987) 使用製造商 (Perbio公司,波恩,德國)推薦的 N-羥基琥珀醯亞胺生物素進行化學生物素化處理。所用珠為 5.6 µm的鏈黴抗生物素蛋白包裹的多聚苯乙烯顆粒(Bangs Labooratories,伊利諾州,美國)。Purified co-stimulatory mouse IgG2a anti-human CD28 antibody 9.3 (Jung et al., 1987) was chemically biotinylated using N-hydroxysuccinimidyl biotin as recommended by the manufacturer (Perbio, Bonn, Germany). The beads used were 5.6 µm streptavidin-coated polystyrene particles (Bangs Laboratories, IL, USA).
用於陽性和陰性對照刺激物的 pMHC 分別為A*0201/MLA-001(從 Melan-A/MART-1中修飾制得的肽ELAGIGILTV (SEQ ID NO.179))和A*0201/DDX5-001(從 DDX5 中獲得的YLLPAIVHI (SEQ ID NO.180))。The pMHC used for positive and negative control stimuli were A*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 179) modified from Melan-A/MART-1) and A*0201/DDX5- 001 (YLLPAIVHI (SEQ ID NO. 180) obtained from DDX5).
800.000 珠/200 µl 包裹於含有 4 x 12.5 ng 不同生物素-pMHC 的 96 孔板、進行洗滌,隨後加入體積為 200 µl 的 600 ng生物素抗-CD28。在 37℃ 下,在含 5 ng/ml IL-12 (PromoCell) 的 200 µl TCM 中共培養 1x10 6CD8+T 細胞與 2x10 5的清洗塗層珠 3 天,從而啟動刺激。之後,一半培養基與補充 80 U/ml IL-2 的新鮮 TCM 進行交換,並且培養在 37℃ 下持續 4 天。這種刺激性週期總共進行 3 次。對於使用每條件 8 種不同 pMHC 分子的 pMHC 多聚體讀出,二維組合編碼方法如前述使用 (Andersen et al., 2012),稍作修飾,涵蓋耦合至 5 種不同的螢光染料。最後,用 Live/dead near IR 染料(Invitrogen公司,Karlsruhe,德國)、CD8-FITC 抗體克隆 SK1(BD公司,Heidelberg,德國)和螢光 pMHC多聚體而執行多聚體分析。對於分析,使用了配有合適鐳射儀和篩檢程序的 BD LSRII SORP 細胞儀。肽特異性細胞以占總 CD8+ 細胞的百分比形式進行計算。多聚體分析結果使用 FlowJo 軟體 (Tree Star 公司,Oregon,美國) 進行評估。特定多聚體+ CD8+淋巴細胞的體外填裝用與陰性對照刺激組比較而進行檢測。如果健康供體中的至少一個可評價的體外刺激孔在體外刺激後發現含有特異性 CD8+ T 細胞株(即該孔包含至少 1% 特定多聚體+ CD8+ T 細胞,並且特定多聚體+的百分比至少為陰性對照刺激中位數的 10 倍),則檢測給定抗原的免疫原性。 胰腺癌肽體外免疫原性 800.000 beads/200 µl were coated in 96-well plates containing 4 x 12.5 ng of various biotin-pMHCs, washed, and then 600 ng biotin anti-CD28 was added in a volume of 200 µl. Stimulation was initiated by co-culturing 1x10 6 CD8+ T cells with 2x10 5 wash-coated beads in 200 µl TCM containing 5 ng/ml IL-12 (PromoCell) for 3 days at 37°C. Afterwards, half of the medium was exchanged with fresh TCM supplemented with 80 U/ml IL-2 and cultured at 37°C for 4 days. This stimulation cycle was performed a total of 3 times. For pMHC multimer readouts using 8 different pMHC molecules per condition, the 2D combinatorial encoding method was used as previously described (Andersen et al., 2012), with slight modifications to cover coupling to 5 different fluorochromes. Finally, multimer analysis was performed with Live/dead near IR dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer with appropriate laser and screening procedures was used. Peptide-specific cells were calculated as a percentage of total CD8+ cells. Multimer analysis results were evaluated using FlowJo software (Tree Star, Oregon, USA). In vitro packing of specific multimer+ CD8+ lymphocytes was tested in comparison to the negative control stimulated group. If at least one evaluable in vitro stimulation well in a healthy donor is found to contain a specific CD8+ T cell line after in vitro stimulation (i.e. the well contains at least 1% specific multimer+ CD8+ T cells and The percentage is at least 10 times the median negative control stimulation) to test the immunogenicity of a given antigen. In vitro immunogenicity of pancreatic cancer peptides
對於受到測試的 HLA-I 類肽,可通過肽特異性 T 細胞株的生成證明其體外免疫原性。TUMAP 特異性多聚體對本發明的 2 種肽染色後流式細胞儀檢測的典型結果如圖 3 所示,同時也含有相應的陰性對照資訊。本發明 4 種肽的結果匯總於表 10A。
表 10 :本發明中 HLA I 類肽的體外免疫原性。申請人對本發明的 HLA-A*02 限制肽所做的體外免疫原性實驗的示例性結果。提示了體外免疫原性實驗的結果。陽性孔和供體(其他可評價)的百分比概括為 <20 % = +;20 % - 49 % = ++;50 % - 69 %= +++;>= 70 %= ++++
所有的肽通過使用 Fmoc 策略以標準、廣為接受的固相肽合成法合成。每個肽的身份和純度已使用質譜和 RP-HPLC 分析法確定。用凍乾法(三氟乙酸鹽)獲得白色至類白色的肽,純度為 >50%。所有的 TUMAP 優選作為三氟乙酸鹽或乙酸鹽進行給藥,其他藥用鹽形式也可以。 實施例 5 MHC 結合測定 All peptides were synthesized by standard, well-accepted solid-phase peptide synthesis using the Fmoc strategy. The identity and purity of each peptide have been determined using mass spectrometry and RP-HPLC analysis. Freeze-drying (trifluoroacetate) afforded the white to off-white peptide with >50% purity. All TUMAPs are preferably administered as trifluoroacetate or acetate salts, but other pharmaceutically acceptable salt forms are also acceptable. Example 5 MHC binding assay
本發明基於 T 細胞療法的候選肽進一步測試其 MHC 結合能力(親和性)。單個肽-MHC 複合體通過 UV-配體交換產生,其中,紫外線敏感肽經紫外線照射後裂解,與分析的相關肽交換。只有能夠有效地結合並穩定肽接受 MHC 分子的候選肽才能阻止 MHC 複合物的解離。為了確定交換反應的產率,將基於穩定 MHC 複合物輕鏈 (β2m) 的檢測結果進行 ELISA 測定。檢測總體上按照 Rodenko 等人在 (Rodenko et al., 2006) 中描述的方法進行。The candidate peptides of the present invention based on T cell therapy were further tested for their MHC binding ability (affinity). Individual peptide-MHC complexes are generated by UV-ligand exchange, in which UV-sensitive peptides are cleaved upon UV irradiation and exchanged with the relevant peptides analyzed. Only candidate peptides that can effectively bind and stabilize peptide-accepting MHC molecules can prevent dissociation of the MHC complex. To determine the yield of the exchange reaction, an ELISA assay was performed based on the detection of the stable MHC complex light chain (β2m). Assays were generally performed as described by Rodenko et al. (Rodenko et al., 2006).
96 孔 Maxisorp 板 (NUNC) 在室溫下在 PBS 中以 2ug/ml 鏈黴包被過夜,用 4 倍洗滌並在37°C 下在含封閉緩衝液的 2% BSA 中封閉 1 小時。折疊的 HLA-A*02:01/MLA-001 單體作為標準品,涵蓋 15-500ng/ml 的範圍。紫外線交換反應的肽-MHC 單體在封閉緩衝液中稀釋100倍。樣本在 37°C下孵育 1 小時,洗滌四次,在 37°C 下以 2ug/ml HRP 綴合抗-β2m 溫育 1 小時,再次洗滌,並以 NH
2SO
4封堵的 TMB 溶液進行檢測。在 450nm 處測量吸收。在生成和產生抗體或其片段時和/或 T 細胞受體或其片段時,通常優選顯示為高交換產率(優選為高於50%,最優選為高於75%)的候選肽,這是因為它們對MHC分子表現出足夠的親合力,並能防止 MHC 複合物的解離。
MHC-I 類結合分數。HLA-I 類限制肽與 HLA-A*02:01 的結合根據肽交換產量分類:≥10% = +; ≥20% = ++; ≥50 = +++; ≥ 75% = ++++
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圖 1A 至 AF顯示了正常組織(白色柱)和胰腺癌(黑色柱)中各種肽的過量表現。圖1A)基因符號:PTGS1,PTGS2,肽:ILIGETIKI (SEQ ID NO.:3),從左至右的組織:1脂肪組織,3腎上腺,6動脈,5骨髓,7大腦, 3乳房,1神經,13結腸,1卵巢,8食管,2膽囊,5心臟,16腎臟,21肝臟,46肺,3淋巴結,4白細胞樣本,3卵巢,4末梢神經,1腹膜,3腦垂體,2胎盤,3 胸膜,3攝護腺,6直肌,7唾液腺,3骨骼肌,5皮膚,2小腸,4脾,7胃,4睾丸,3 胸腺,4甲狀腺,7氣管,3輸尿管, 6膀胱,2子宮,2靜脈,7胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還在4/91肺癌,1/20卵巢癌,1/24結直腸癌,1/18腎癌症和1/4膀胱癌中檢測出(未列出)。圖1B)基因符號:COL1A2,肽:FVDTRTLL (SEQ ID NO.:1),從左至右的組織:1脂肪組織,3腎上腺,6動脈,5骨髓,7大腦 3乳房,1神經,13結腸,1卵巢,8食管,2膽囊,5心臟,16腎臟,21肝臟,46肺,3淋巴結,4白細胞樣本,3卵巢,4末梢神經,1腹膜,3腦垂體,2胎盤,3 胸膜,3攝護腺,6直肌,7唾液腺,3骨骼肌,5皮膚,2小腸,4脾,7胃,4睾丸,3 胸腺,4甲狀腺,7氣管,3輸尿管, 6膀胱,2子宮,2靜脈,7胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還在 3/91肺癌和1/17食管癌中檢測出。圖1C)基因符號:PTPN14,肽:AQYKFVYQV (SEQ ID NO.:12),從左至右的組織:1脂肪組織,3腎上腺,6動脈,5骨髓,7大腦 3乳房,1神經,13結腸,1卵巢,8食管,2膽囊,5心臟,16腎臟,21肝臟,46肺,3淋巴結,4白細胞樣本,3卵巢,4末梢神經,1腹膜,3腦垂體,2胎盤,3 胸膜,3攝護腺,6直肌,7唾液腺,3骨骼肌,5皮膚,2小腸,4脾,7胃,4睾丸,3 胸腺,4甲狀腺,7氣管,3輸尿管, 6膀胱,2子宮,2靜脈,7胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還在 1/20卵巢癌,2/17食道癌,1/46胃癌,1/91肺癌和1/18腎癌中檢測出。圖1D)基因符號:UBR1,肽:SLMDPNKFLLL (SEQ ID NO.:115),從左至右的組織:13胰腺細胞系,2 PBMC培養物,1攝護腺細胞培養物,3皮膚細胞系,7正常組織(1肝,2肺,2脾臟,1胃,1氣管),62癌組織(8腦癌,2乳腺癌,2結腸癌,1食道癌,1膽囊癌,5腎癌,3白血病,6肝癌,19肺癌,5卵巢癌,1胰腺癌,3攝護腺癌,3直腸癌,1皮膚癌,2膀胱癌)。正常組織系列(無病)和癌症細胞系和測試的異種移植物與圖1A-C 相同,包括1脂肪組織,3腎上腺,6動脈,5骨髓,7大腦 3乳房,1神經,13結腸,1卵巢,8食管,2膽囊,5心臟,16腎臟,21肝臟,46肺,3淋巴結,4白細胞樣本,3卵巢,4末梢神經,1腹膜,3腦垂體,2胎盤,3 胸膜,3攝護腺,6直肌,7唾液腺,3骨骼肌,5皮膚,2小腸,4脾,7胃,4睾丸,3 胸腺,4甲狀腺,7氣管,3輸尿管, 6膀胱,2子宮,2靜脈,7胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還在1/6乳腺癌,5/24結直腸癌,1/2膽囊/膽道癌,6/16肝癌,1/2黑色素瘤,5/20卵巢癌,1/17食管癌,3/12白血病,7/29腦癌,16/91非小細胞肺癌,3/33攝護腺癌,3/18腎癌,3/14小細胞肺癌和1/4膀胱癌上檢測到。圖 1D 和表 4 之間的腫瘤類型相關的差異可能是由於表 4 採用更嚴格的選擇標準所致(詳情請參照表 4)。圖 1D 顯示了可檢測表現 肽 Y 的所有樣本,無論過度表現參數和技術樣本品質測試如何。圖1E)基因符號:NUP205,肽:ALLTGIISKA (SEQ ID NO.:5),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/34腦癌,1/18乳腺癌,2/29結腸或直腸癌,1/18食管癌,1/8頭頸部癌,1/21肝癌, 8/107 肺癌,1/20淋巴結癌,1/20卵巢癌,1/18皮膚癌,2/15膀胱癌,1/16子宮癌。圖1F)基因符號:NUP160,肽:ALWHDAENQTVV (SEQ ID NO.:19),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/17膽囊或膽管癌,2/34腦癌,1/18乳腺癌,1/18食管癌,1/21肝癌,8/107肺癌,2/18皮膚癌,2/15膀胱癌,1/16子宮癌。圖1G)基因符號:C11orf80,肽:ILSTEIFGV (SEQ ID NO.:22),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於3/18乳腺癌,1/17膽囊癌,1/8頭頸部癌,5/17白細胞白血病,6/107肺癌,4/20淋巴結癌,1/20卵巢癌,1/19胰腺癌,1/18皮膚癌,1/21胃癌。圖1H)基因符號:FAM83D,肽:FLNPDEVHAI (SEQ ID NO.:37),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/17膽囊或膽管癌,2/34腦癌,3/18乳腺癌,6/29結腸或直腸癌,2/18食管癌,2/8頭頸部癌, 1/23腎癌,5/21肝癌,25/107肺癌,4/20淋巴結癌,7/20卵巢癌,1/87攝護腺癌,2/18皮膚癌,2/45胃癌,6/15膀胱癌,3/16子宮癌。圖1I)基因符號:DCBLD2,肽:TMVEHNYYV (SEQ ID NO.:46),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於1/18食管癌,1/17膽囊癌,1/8頭頸部癌,3/23腎癌,9/107肺癌,7/20卵巢癌,1/19胰腺癌,1/18皮膚癌,1/45胃癌,2/15膀胱癌,1/16子宮癌。圖1J)基因符號:SHCBP1,肽:RLSELGITQA (SEQ ID NO.:57),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於1/34腦癌,1/18乳腺癌,2/18食管癌,2/8頭頸部癌,1/21肝癌,8/107肺癌,4/20淋巴結癌,1/18骨髓細胞癌,4/20卵巢癌,4/18皮膚癌,2/15膀胱癌,1/16子宮癌。圖1K)基因符號:CTHRC1,肽:VLFSGSLRL (SEQ ID NO.:69),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於 2/18乳腺癌,1/18食管癌,1/17膽囊癌,9/107 肺癌,1/20卵巢癌。圖1L)基因符號:CDC27,肽:KISTITPQI (SEQ ID NO.:123),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/34腦癌,2/8頭頸部癌,1/23腎癌,1/17白細胞白血病,2/21肝癌,7/107肺癌,2/20淋巴結癌,1/18髓樣細胞癌,1/18皮膚癌,1/45胃癌,2/15膀胱癌,3/16子宮癌。圖1M)基因符號:UBE2C,肽:ALYDVRTILL (SEQ ID NO.:128),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/18乳腺癌,3/29結腸或直腸癌,1/17白細胞白血病,18/107肺癌,1/20淋巴結癌,1/20卵巢癌,1/15膀胱癌。圖1N)基因符號:MBTPS2,肽:VLISGVVHEI (SEQ ID NO.:146),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於7/34腦癌,1/18乳腺癌,2/29結腸或直腸癌,1/18食管癌,1/23腎癌,3/21肝癌,5/107肺癌,1/20淋巴結癌,2/20卵巢癌,1/87攝護腺癌,3/18皮膚癌,1/16子宮癌。圖1O)基因符號:PFDN1,肽:KLADIQIEQL (SEQ ID NO.:89),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於2/29結腸或直腸癌,1/17白細胞白血病,4/107肺癌,4/20卵巢癌,4/16膀胱癌。圖1P)基因符號:PKP3,肽:ALVEENGIFEL (SEQ ID NO.:101),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於1/17膽管癌,2/18乳腺癌,2/29結腸或直腸癌,2/18食管癌,2/8頭頸部癌,1/21肝癌,7/107肺癌,6/20卵巢癌,3/87攝護腺癌,4/15膀胱癌,1/16子宮癌。圖1Q)基因符號:GFPT2,肽:LMMSEDRISL (SEQ ID NO.:113),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於3/17膽囊或膽管癌,5/34腦癌,3/18乳腺癌,2/29結腸或直腸癌,2/18食管癌,1/8頭頸部癌, 1/21肝癌,18/107肺癌,3/20淋巴結癌,1/19胰腺癌,1/87攝護腺癌,2/18皮膚癌,2/15膀胱癌,1/16子宮癌。圖1R)基因符號:CCT4,肽:ALSDLALHFL (SEQ ID NO.:127),從左至右的組織:6脂肪組織,8腎上腺,24血細胞,15血管,10骨髓,14大腦,7乳房,9食管,2眼,3膽囊,16心臟,17腎臟,23大腸,23肝,49肺,7淋巴結,12神經,2卵巢,6甲狀旁腺,1腹膜,6腦垂體,7胎盤,1胸膜,3攝護腺,7唾液腺,10骨骼肌,11皮膚,8小腸,12脾,7胃,5睾丸,3 胸腺,3甲狀腺,15氣管,7輸尿管,8膀胱,6子宮,10胰腺,20胰腺癌細胞系和異種移植物樣本。該肽還發現於1/34腦癌,2/18乳腺癌,2/8頭頸部癌,3/17白細胞白血病,1/21肝癌, 3/107肺癌,4/20淋巴結癌,2/18髓樣細胞癌,1/20卵巢癌,3/18皮膚癌,4/15膀胱癌。圖1S)基因符號:NUP205,肽:ALLTGIISKA (SEQ ID NO.:5),從左至右的組織:12癌細胞系,1正常組織(1脾),22癌組織(2腦癌, 1乳腺癌,1結腸癌,1食管癌,1頭頸癌,1肝癌,8肺癌,1淋巴結癌,1卵巢癌,1直腸癌,1皮膚癌,2膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1T) 基因符號:NUP160,肽:ALWHDAENQTVV (SEQ ID NO.:19),從左至右的組織:13癌細胞系,1原代培養物,1正常組織(1脾),20癌組織(1膽管癌,2腦癌,1乳腺癌,1食管癌,1膽囊癌,1肝癌,8肺癌,2皮膚癌,2膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1U) 基因符號:C11orf80,肽:ILSTEIFGV (SEQ ID NO.:22),從左至右的組織:1癌細胞系,3原代培養物,1正常組織(1淋巴結),24癌組織(3乳腺癌,1膽囊癌,1頭頸癌,5白細胞白血病,6肺癌,4淋巴結癌,1卵巢癌,1胰腺癌,1皮膚癌,1胃癌)。測試的正常組織系列與圖 1E-R 中相同。圖1V) 基因符號:FAM83D,肽:FLNPDEVHAI (SEQ ID NO.:37),從左至右的組織:16癌細胞系,3原代培養物,1正常組織(1氣管),73癌組織(1膽管癌,2腦癌,3乳腺癌,4結腸癌,2食管癌,1膽囊癌,2頭頸癌,1腎癌,5肝癌,25肺癌,4淋巴結癌,7卵巢癌,1攝護腺癌,2直腸癌,2皮膚癌,2胃癌,6膀胱癌,3子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1W) 基因符號:DCBLD2,肽:TMVEHNYYV (SEQ ID NO.:46),從左至右的組織:4癌細胞系,1原代培養物,28癌組織(1食管癌,1膽囊癌, 1頭頸癌,3腎癌,9肺癌,7卵巢癌,1胰腺癌,1皮膚癌,1胃癌,2膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1X) 基因符號:SHCBP1,肽:RLSELGITQA (SEQ ID NO.:57),從左至右的組織:20癌細胞系,2原代培養物,2正常組織(1骨髓,1胎盤), 31癌組織 (1腦癌,1乳腺癌,2食管癌,2頭頸癌,1肝癌,8肺癌,4淋巴結癌,1骨髓細胞癌,4卵巢癌,4皮膚癌,2膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1Y) 基因符號:CTHRC1,肽:VLFSGSLRL (SEQ ID NO.:69),從左至右的組織:5癌細胞系,14癌組織(2乳腺癌,1食管癌,1膽囊癌, 9肺癌,1卵巢癌)。測試的正常組織系列與圖 1E-R 中相同。圖1Z) 基因符號:CDC27,肽:KISTITPQI (SEQ ID NO.:123),從左至右的組織:19癌細胞系,2原代培養物,3正常組織(1腎上腺,1肝臟,1胎盤),25癌組織(2腦癌,2頭頸癌,1腎癌,1白細胞白血病,2肝癌,7肺癌,2淋巴結癌,1骨髓細胞癌,1皮膚癌,1胃癌,2膀胱癌,3子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AA) 基因符號:UBE2C,肽:ALYDVRTILL (SEQ ID NO.:128),從左至右的組織:10癌細胞系,17癌組織(2乳腺癌,1盲腸癌,2結腸癌,1白細胞白血病,8肺癌,1淋巴結癌,1卵巢癌,1膀胱癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AB) 基因符號:MBTPS2,肽:VLISGVVHEI (SEQ ID NO.:146),從左至右的組織:16癌細胞系,2原代培養物,2正常組織(1脾臟,1子宮),28癌組織(7腦癌,1乳腺癌,2結腸癌,1食管癌,1腎癌,3肝癌,5肺癌,1淋巴結癌,2卵巢癌,1攝護腺癌,3皮膚癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AC) 基因符號:PFDN1,肽:KLADIQIEQL (SEQ ID NO.:89),從左至右的組織:11癌細胞系,2正常組織(2腎上腺),15癌組織(2結腸癌,1白細胞白血病,4肺癌,4卵巢癌,4膀胱癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AD) 基因符號:PKP3,肽:ALVEENGIFEL (SEQ ID NO.:101),從左至右的組織:3癌細胞系,3原代培養物,2正常組織(2結腸),31癌組織( 1膽管癌,2乳腺癌,1盲腸癌,1結腸癌,2食管癌,2頭頸癌,1肝癌,7肺癌,6卵巢癌,3攝護腺癌,4膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AE) 基因符號:GFPT2,肽:LMMSEDRISL (SEQ ID NO.:113),從左至右的組織:8癌細胞系,1正常組織(1眼),45癌組織(1膽管癌,5腦癌,3乳腺癌,1結腸癌,2食管癌,2膽囊癌,1頭頸癌,1肝癌,18肺癌,3淋巴結癌,1胰腺癌,1攝護腺癌,1直腸癌,2皮膚癌,2膀胱癌,1子宮癌)。測試的正常組織系列與圖 1E-R 中相同。圖1AF) 基因符號:CCT4,肽:ALSDLALHFL (SEQ ID NO.:127),從左至右的組織:9癌細胞系,26癌組織(1骨髓癌,1腦癌,2乳腺癌,2頭頸癌,3白細胞白血病,1肝癌,3肺癌,4淋巴結癌,1骨髓細胞癌,1卵巢癌,3皮膚癌,4膀胱癌)。測試的正常組織系列與圖 1E-R 中相同。 Figures 1A to AF show the overexpression of various peptides in normal tissue (white bars) and pancreatic cancer (black bars). Figure 1A) Gene symbols: PTGS1, PTGS2, peptide: ILIGETIKI (SEQ ID NO.: 3), tissues from left to right: 1 adipose tissue, 3 adrenal gland, 6 arteries, 5 bone marrow, 7 brain, 3 breast, 1 nerve , 13 colon, 1 ovary, 8 esophagus, 2 gallbladder, 5 heart, 16 kidney, 21 liver, 46 lung, 3 lymph node, 4 leukocyte sample, 3 ovary, 4 peripheral nerve, 1 peritoneum, 3 pituitary gland, 2 placenta, 3 pleura , 3 prostate, 6 rectus, 7 salivary gland, 3 skeletal muscle, 5 skin, 2 small intestine, 4 spleen, 7 stomach, 4 testis, 3 thymus, 4 thyroid, 7 trachea, 3 ureter, 6 bladder, 2 uterus, 2 veins, 7 pancreas, 20 pancreatic cancer cell lines and xenograft samples. The peptide was also detected in 4/91 lung cancer, 1/20 ovarian cancer, 1/24 colorectal cancer, 1/18 kidney cancer and 1/4 bladder cancer (not listed). Figure 1B) Gene symbol: COL1A2, Peptide: FVDTRTLL (SEQ ID NO.: 1), tissues from left to right: 1 adipose tissue, 3 adrenal gland, 6 arteries, 5 bone marrow, 7 brain, 3 breast, 1 nerve, 13 colon , 1 ovary, 8 esophagus, 2 gallbladder, 5 heart, 16 kidney, 21 liver, 46 lung, 3 lymph node, 4 leukocyte samples, 3 ovary, 4 peripheral nerves, 1 peritoneum, 3 pituitary gland, 2 placenta, 3 pleura, 3 photographic Gland, 6 rectus, 7 salivary gland, 3 skeletal muscle, 5 skin, 2 small intestine, 4 spleen, 7 stomach, 4 testis, 3 thymus, 4 thyroid, 7 trachea, 3 ureter, 6 bladder, 2 uterus, 2 vein, 7 pancreas, 20 pancreatic cancer cell lines and xenograft samples. The peptide was also detected in 3/91 lung cancers and 1/17 esophageal cancers. Figure 1C) Gene symbol: PTPN14, Peptide: AQYKFVYQV (SEQ ID NO.: 12), tissues from left to right: 1 adipose tissue, 3 adrenal gland, 6 arteries, 5 bone marrow, 7 brain, 3 breast, 1 nerve, 13 colon , 1 ovary, 8 esophagus, 2 gallbladder, 5 heart, 16 kidney, 21 liver, 46 lung, 3 lymph node, 4 leukocyte samples, 3 ovary, 4 peripheral nerves, 1 peritoneum, 3 pituitary gland, 2 placenta, 3 pleura, 3 photographic Gland, 6 rectus, 7 salivary gland, 3 skeletal muscle, 5 skin, 2 small intestine, 4 spleen, 7 stomach, 4 testis, 3 thymus, 4 thyroid, 7 trachea, 3 ureter, 6 bladder, 2 uterus, 2 vein, 7 pancreas, 20 pancreatic cancer cell lines and xenograft samples. The peptide was also detected in 1/20 ovarian cancer, 2/17 esophageal cancer, 1/46 gastric cancer, 1/91 lung cancer and 1/18 renal cancer. Figure 1D) Gene symbol: UBR1, peptide: SLMDPNKFLLL (SEQ ID NO.: 115), tissue from left to right: 13 pancreatic cell lines, 2 PBMC cultures, 1 prostate cell culture, 3 skin cell lines, 7 Normal tissues (1 liver, 2 lungs, 2 spleen, 1 stomach, 1 trachea), 62 cancer tissues (8 brain cancer, 2 breast cancer, 2 colon cancer, 1 esophagus cancer, 1 gallbladder cancer, 5 kidney cancer, 3 leukemia, 6 liver cancer, 19 lung cancer, 5 ovarian cancer, 1 pancreatic cancer, 3 prostate cancer, 3 rectal cancer, 1 skin cancer, 2 bladder cancer). Normal tissue series (no disease) and cancer cell lines and xenografts tested were the same as in Figure 1A-C, including 1 adipose tissue, 3 adrenal gland, 6 arteries, 5 bone marrow, 7 brain, 3 breast, 1 nerve, 13 colon, 1 ovary , 8 esophagus, 2 gallbladder, 5 heart, 16 kidney, 21 liver, 46 lung, 3 lymph node, 4 leukocyte sample, 3 ovary, 4 peripheral nerve, 1 peritoneum, 3 pituitary gland, 2 placenta, 3 pleura, 3 prostate, 6 rectus muscle, 7 salivary gland, 3 skeletal muscle, 5 skin, 2 small intestine, 4 spleen, 7 stomach, 4 testis, 3 thymus, 4 thyroid, 7 trachea, 3 ureter, 6 bladder, 2 uterus, 2 vein, 7 pancreas, 20 pancreatic cancer cell lines and xenograft samples. The peptide is also present in 1/6 breast cancer, 5/24 colorectal cancer, 1/2 gallbladder/biliary tract cancer, 6/16 liver cancer, 1/2 melanoma, 5/20 ovarian cancer, 1/17 esophageal cancer, 3 /12 leukemia, 7/29 brain cancer, 16/91 non-small cell lung cancer, 3/33 prostate cancer, 3/18 kidney cancer, 3/14 small cell lung cancer and 1/4 bladder cancer were detected. The tumor type-related differences between Figure 1D and Table 4 may be due to the stricter selection criteria used in Table 4 (see Table 4 for details). Figure 1D shows all samples that can detectably express peptide Y, regardless of over-performance parameters and technical sample quality tests. Figure 1E) Gene symbol: NUP205, peptide: ALLTGIISKA (SEQ ID NO.: 5), from left to right tissues: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/34 brain cancer, 1/18 breast cancer, 2/29 colon or rectal cancer, 1/18 esophageal cancer, 1/8 head and neck cancer, 1/21 liver cancer, 8/107 lung cancer, 1/ 20 lymph node cancer, 1/20 ovarian cancer, 1/18 skin cancer, 2/15 bladder cancer, 1/16 uterine cancer. Figure 1F) Gene symbol: NUP160, Peptide: ALWHDAENQTVV (SEQ ID NO.: 19), Tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/17 gallbladder or bile duct cancer, 2/34 brain cancer, 1/18 breast cancer, 1/18 esophageal cancer, 1/21 liver cancer, 8/107 lung cancer, 2/18 skin cancer, 2/15 Bladder cancer, 1/16 uterine cancer. Figure 1G) Gene symbol: C11orf80, Peptide: ILSTEIFGV (SEQ ID NO.: 22), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 3/18 breast cancer, 1/17 gallbladder cancer, 1/8 head and neck cancer, 5/17 leukemia, 6/107 lung cancer, 4/20 lymph node cancer, 1/20 ovarian cancer, 1/19 Pancreatic cancer, 1/18 skin cancer, 1/21 stomach cancer. Figure 1H) Gene symbol: FAM83D, peptide: FLNPDEVHAI (SEQ ID NO.: 37), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/17 gallbladder or bile duct cancer, 2/34 brain cancer, 3/18 breast cancer, 6/29 colon or rectal cancer, 2/18 esophageal cancer, 2/8 head and neck cancer, 1/23 kidney cancer Cancer, 5/21 Liver Cancer, 25/107 Lung Cancer, 4/20 Lymph Node Cancer, 7/20 Ovarian Cancer, 1/87 Prostate Cancer, 2/18 Skin Cancer, 2/45 Gastric Cancer, 6/15 Bladder Cancer, 3 /16 Uterine cancer. Figure 1I) Gene symbol: DCBLD2, peptide: TMVEHNYYV (SEQ ID NO.: 46), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 1/18 esophageal cancer, 1/17 gallbladder cancer, 1/8 head and neck cancer, 3/23 kidney cancer, 9/107 lung cancer, 7/20 ovarian cancer, 1/19 pancreatic cancer, 1/18 Skin cancer, 1/45 stomach cancer, 2/15 bladder cancer, 1/16 uterine cancer. Figure 1J) Gene symbol: SHCBP1, Peptide: RLSELGITQA (SEQ ID NO.: 57), Tissue from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide is also found in 1/34 brain cancer, 1/18 breast cancer, 2/18 esophageal cancer, 2/8 head and neck cancer, 1/21 liver cancer, 8/107 lung cancer, 4/20 lymph node cancer, 1/18 bone marrow cancer Cell cancer, 4/20 ovarian cancer, 4/18 skin cancer, 2/15 bladder cancer, 1/16 uterine cancer. Figure 1K) Gene symbol: CTHRC1, peptide: VLFSGSLRL (SEQ ID NO.: 69), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/18 breast cancer, 1/18 esophageal cancer, 1/17 gallbladder cancer, 9/107 lung cancer, and 1/20 ovarian cancer. Figure 1L) Gene symbol: CDC27, Peptide: KISTITPQI (SEQ ID NO.: 123), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/34 brain cancer, 2/8 head and neck cancer, 1/23 kidney cancer, 1/17 leukemia, 2/21 liver cancer, 7/107 lung cancer, 2/20 lymph node cancer, 1/18 medullary cancer Like cell carcinoma, 1/18 skin cancer, 1/45 stomach cancer, 2/15 bladder cancer, 3/16 uterine cancer. Figure 1M) Gene symbol: UBE2C, Peptide: ALYDVRTILL (SEQ ID NO.: 128), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/18 breast cancer, 3/29 colon or rectal cancer, 1/17 leukemia, 18/107 lung cancer, 1/20 lymph node cancer, 1/20 ovarian cancer, 1/15 bladder cancer. Figure 1N) Gene symbol: MBTPS2, Peptide: VLISGVVHEI (SEQ ID NO.: 146), Tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 7/34 brain cancer, 1/18 breast cancer, 2/29 colon or rectal cancer, 1/18 esophageal cancer, 1/23 kidney cancer, 3/21 liver cancer, 5/107 lung cancer, 1/20 Lymph node cancer, 2/20 ovarian cancer, 1/87 prostate cancer, 3/18 skin cancer, 1/16 uterine cancer. Figure 1O) Gene Symbol: PFDN1, Peptide: KLADIQIEQL (SEQ ID NO.: 89), Tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 2/29 colon or rectal cancer, 1/17 leukemia, 4/107 lung cancer, 4/20 ovarian cancer, 4/16 bladder cancer. Figure 1P) Gene Symbol: PKP3, Peptide: ALVEENGIFEL (SEQ ID NO.: 101), Tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 1/17 cholangiocarcinoma, 2/18 breast cancer, 2/29 colon or rectal cancer, 2/18 esophageal cancer, 2/8 head and neck cancer, 1/21 liver cancer, 7/107 lung cancer, 6/ 20 ovarian cancer, 3/87 prostate cancer, 4/15 bladder cancer, 1/16 uterine cancer. Figure 1Q) Gene symbol: GFPT2, Peptide: LMMSEDRISL (SEQ ID NO.: 113), tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 3/17 gallbladder or bile duct cancer, 5/34 brain cancer, 3/18 breast cancer, 2/29 colon or rectal cancer, 2/18 esophageal cancer, 1/8 head and neck cancer, 1/21 liver cancer , 18/107 lung cancer, 3/20 lymph node cancer, 1/19 pancreatic cancer, 1/87 prostate cancer, 2/18 skin cancer, 2/15 bladder cancer, 1/16 uterine cancer. Figure 1R) Gene symbol: CCT4, Peptide: ALSDLALHFL (SEQ ID NO.: 127), Tissues from left to right: 6 adipose tissue, 8 adrenal gland, 24 blood cells, 15 blood vessels, 10 bone marrow, 14 brain, 7 breast, 9 Esophagus, 2 eyes, 3 gallbladder, 16 heart, 17 kidney, 23 large intestine, 23 liver, 49 lung, 7 lymph node, 12 nerve, 2 ovary, 6 parathyroid gland, 1 peritoneum, 6 pituitary gland, 7 placenta, 1 pleura , 3 prostate, 7 salivary glands, 10 skeletal muscle, 11 skin, 8 small intestine, 12 spleen, 7 stomach, 5 testes, 3 thymus, 3 thyroid, 15 trachea, 7 ureter, 8 bladder, 6 uterus, 10 pancreas, 20 Pancreatic cancer cell lines and xenograft samples. The peptide was also found in 1/34 brain cancer, 2/18 breast cancer, 2/8 head and neck cancer, 3/17 leukemia, 1/21 liver cancer, 3/107 lung cancer, 4/20 lymph node cancer, 2/18 medullary cancer Like cell carcinoma, 1/20 ovarian cancer, 3/18 skin cancer, 4/15 bladder cancer. Figure 1S) Gene symbol: NUP205, peptide: ALLTGIISKA (SEQ ID NO.: 5), tissues from left to right: 12 cancer cell lines, 1 normal tissue (1 spleen), 22 cancer tissues (2 brain cancer, 1 breast cancer) cancer, 1 colon cancer, 1 esophageal cancer, 1 head and neck cancer, 1 liver cancer, 8 lung cancer, 1 lymph node cancer, 1 ovarian cancer, 1 rectal cancer, 1 skin cancer, 2 bladder cancer, 1 uterine cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1T) Gene symbol: NUP160, peptide: ALWHDAENQTVV (SEQ ID NO.: 19), tissues from left to right: 13 cancer cell lines, 1 primary culture, 1 normal tissue (1 spleen), 20 cancer tissue ( 1 Cholangiocarcinoma, 2 Brain Cancer, 1 Breast Cancer, 1 Esophageal Cancer, 1 Gallbladder Cancer, 1 Liver Cancer, 8 Lung Cancer, 2 Skin Cancer, 2 Bladder Cancer, 1 Uterine Cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1U) Gene symbol: C11orf80, peptide: ILSTEIFGV (SEQ ID NO.: 22), tissues from left to right: 1 cancer cell line, 3 primary cultures, 1 normal tissue (1 lymph node), 24 cancer tissue ( 3 breast cancer, 1 gallbladder cancer, 1 head and neck cancer, 5 leukemia, 6 lung cancer, 4 lymph node cancer, 1 ovarian cancer, 1 pancreatic cancer, 1 skin cancer, 1 gastric cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1V) Gene symbol: FAM83D, peptide: FLNPDEVHAI (SEQ ID NO.: 37), tissues from left to right: 16 cancer cell lines, 3 primary cultures, 1 normal tissue (1 trachea), 73 cancer tissues ( 1 Cholangiocarcinoma, 2 Brain Cancer, 3 Breast Cancer, 4 Colon Cancer, 2 Esophageal Cancer, 1 Gallbladder Cancer, 2 Head and Neck Cancer, 1 Kidney Cancer, 5 Liver Cancer, 25 Lung Cancer, 4 Lymph Node Cancer, 7 Ovarian Cancer, 1 Prostate Cancer cancer, 2 rectal cancer, 2 skin cancer, 2 stomach cancer, 6 bladder cancer, 3 uterine cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1W) Gene symbol: DCBLD2, peptide: TMVEHNYYV (SEQ ID NO.: 46), tissues from left to right: 4 cancer cell lines, 1 primary culture, 28 cancer tissues (1 esophageal cancer, 1 gallbladder cancer, 1 head and neck cancer, 3 kidney cancer, 9 lung cancer, 7 ovarian cancer, 1 pancreatic cancer, 1 skin cancer, 1 stomach cancer, 2 bladder cancer, 1 uterine cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1X) Gene symbol: SHCBP1, peptide: RLSELGITQA (SEQ ID NO.: 57), tissues from left to right: 20 cancer cell lines, 2 primary cultures, 2 normal tissues (1 bone marrow, 1 placenta), 31 Cancer tissue (1 brain cancer, 1 breast cancer, 2 esophageal cancer, 2 head and neck cancer, 1 liver cancer, 8 lung cancer, 4 lymph node cancer, 1 bone marrow cell cancer, 4 ovarian cancer, 4 skin cancer, 2 bladder cancer, 1 uterine cancer) . The normal tissue series tested were the same as in Figure 1E-R. Figure 1Y) Gene symbol: CTHRC1, peptide: VLFSGSLRL (SEQ ID NO.: 69), tissues from left to right: 5 cancer cell lines, 14 cancer tissues (2 breast cancer, 1 esophageal cancer, 1 gallbladder cancer, 9 lung cancer , 1 ovarian cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1Z) Gene symbol: CDC27, Peptide: KISTITPQI (SEQ ID NO.: 123), tissues from left to right: 19 cancer cell lines, 2 primary cultures, 3 normal tissues (1 adrenal gland, 1 liver, 1 placenta ), 25 cancer tissues (2 brain cancer, 2 head and neck cancer, 1 kidney cancer, 1 leukemia, 2 liver cancer, 7 lung cancer, 2 lymph node cancer, 1 bone marrow cancer, 1 skin cancer, 1 stomach cancer, 2 bladder cancer, 3 uterine cancer cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AA) Gene symbol: UBE2C, peptide: ALYDVRTILL (SEQ ID NO.: 128), tissues from left to right: 10 cancer cell lines, 17 cancer tissues (2 breast cancer, 1 cecal cancer, 2 colon cancer, 1 leukocyte leukemia, 8 lung cancer, 1 lymph node cancer, 1 ovarian cancer, 1 bladder cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AB) Gene symbol: MBTPS2, peptide: VLISGVVHEI (SEQ ID NO.: 146), tissues from left to right: 16 cancer cell lines, 2 primary cultures, 2 normal tissues (1 spleen, 1 uterus), 28 Cancer tissues (7 brain cancer, 1 breast cancer, 2 colon cancer, 1 esophagus cancer, 1 kidney cancer, 3 liver cancer, 5 lung cancer, 1 lymph node cancer, 2 ovarian cancer, 1 prostate cancer, 3 skin cancer, 1 uterine cancer ). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AC) Gene symbol: PFDN1, peptide: KLADIQIEQL (SEQ ID NO.: 89), tissues from left to right: 11 cancer cell lines, 2 normal tissues (2 adrenal glands), 15 cancer tissues (2 colon cancer, 1 leukocyte leukemia, 4 lung cancer, 4 ovarian cancer, 4 bladder cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AD) Gene symbol: PKP3, Peptide: ALVEENGIFEL (SEQ ID NO.: 101), tissues from left to right: 3 cancer cell lines, 3 primary cultures, 2 normal tissues (2 colon), 31 cancer tissues ( 1 bile duct cancer, 2 breast cancer, 1 cecal cancer, 1 colon cancer, 2 esophageal cancer, 2 head and neck cancer, 1 liver cancer, 7 lung cancer, 6 ovarian cancer, 3 prostate cancer, 4 bladder cancer, 1 uterine cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AE) Gene symbol: GFPT2, peptide: LMMSEDRISL (SEQ ID NO.: 113), tissues from left to right: 8 cancer cell lines, 1 normal tissue (1 eye), 45 cancer tissues (1 cholangiocarcinoma, 5 brain Cancer, 3 Breast Cancer, 1 Colon Cancer, 2 Esophageal Cancer, 2 Gallbladder Cancer, 1 Head and Neck Cancer, 1 Liver Cancer, 18 Lung Cancer, 3 Lymph Node Cancer, 1 Pancreatic Cancer, 1 Prostate Cancer, 1 Rectal Cancer, 2 Skin Cancer, 2 bladder cancer, 1 uterine cancer). The normal tissue series tested were the same as in Figure 1E-R. Figure 1AF) Gene symbol: CCT4, peptide: ALSDLALHFL (SEQ ID NO.: 127), tissues from left to right: 9 cancer cell lines, 26 cancer tissues (1 bone marrow cancer, 1 brain cancer, 2 breast cancer, 2 head and neck cancer carcinoma, 3 leukocyte leukemia, 1 liver cancer, 3 lung cancer, 4 lymph node cancer, 1 bone marrow cancer, 1 ovarian cancer, 3 skin cancer, 4 bladder cancer). The normal tissue series tested were the same as in Figure 1E-R.
圖2A 至 C顯示了本發明的源基因的代表性表達特徵(與正常胰腺相比的相對表達),這些基因在一系列正常組織(白色柱)胰腺癌中以及 9 份胰腺癌樣本(黑色柱)中高度過度表達或專門表達。從左到右的組織:腎上腺、動脈、骨髓、腦(全部)、乳腺、結腸、食管、心臟、腎(三份)、白細胞、肝、肺、淋巴結、卵巢、胰腺、胎盤、攝護腺、唾液腺腺、骨骼肌、皮膚、小腸、脾、胃、睾丸、胸腺、甲狀腺、膀胱、宮頸、子宮、靜脈、9 個胰腺癌樣本。圖 2A) SHCBP1;圖 2B) FN1;和圖 2C) PLEC。Figures 2A to C show representative expression profiles (relative expression compared to normal pancreas) of the source genes of the invention in a series of normal tissue (white bars) pancreatic cancer and 9 pancreatic cancer samples (black bars). ) is highly overexpressed or exclusively expressed. Tissues from left to right: adrenal glands, arteries, bone marrow, brain (all), breast, colon, esophagus, heart, kidneys (triplicates), leukocytes, liver, lungs, lymph nodes, ovaries, pancreas, placenta, prostate, Salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, testis, thymus, thyroid, bladder, cervix, uterus, vein, 9 pancreatic cancer samples. Figure 2A) SHCBP1; Figure 2B) FN1; and Figure 2C) PLEC.
圖 3A 至 D 顯示了示例性的免疫原性資料:肽特定多聚體染色後流式細胞儀結果。CD8+ T 細胞製備的方法為:使用抗CD28 mAb 和 HLA-A*02 塗層的人工 APC 分別與 SeqID No 125 肽(A,左圖)、SeqID No 148 肽(B,左圖)、SeqID No 156 肽(C,左圖)、SeqID No 178 肽(D,左上圖)和 SeqID No 177 肽(D,左下圖)合成。經過 3 個週期的刺激後,用 A*02/SeqID No 125 (A)、A*02/SeqID No 148 (B) 或 A*02/SeqID No 156 (C) 的 2D 多聚體染色法對肽反應性細胞進行檢測。右圖(A、B、C 和 D)顯示用不相關A*02/肽複合體刺激的細胞對照染色。活單細胞在 CD8+ 淋巴細胞上得到門控。Boolean門控幫助排除用不同肽特定的多聚體檢測的假陽性事件。提示了特異性多聚體+ 細胞和 CD8+ 淋巴細胞的頻率。Figures 3A through D show exemplary immunogenicity profiles: flow cytometry results after peptide-specific multimer staining. CD8+ T cells were prepared by using anti-CD28 mAb and HLA-A*02-coated artificial APCs with
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